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NIDDK Strategic Plan 2000

DRAFT 01/10/00

• Message from the Director
• About the NIDDK
• Magnitude of Challenges
• About the Planning Process
• Strategic Plan

Message from the Director, NIDDK

As the new Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), I am pleased to present to you our Institute's first five-year Strategic Plan. The strategies outlined in this plan speak to the opportunities and challenges facing our Institute, and are the product of the NIDDK's senior scientific management team, working in collaboration with the National Advisory Council, the scientific community at large, lay and professional organizations, and the public.

All agree that much is at stake. The many diseases within the NIDDK's research mission affect millions of individuals of all ages, are often chronic in nature, may cause significant morbidity, reduce life expectancy, and exert an enormous economic burden on society--in excess of $300 billion annually.

It is our expectation that the successful implementation of our Strategic Plan will enable the NIDDK to harness the tools, technologies, and talent needed to further understand, treat, and prevent the diseases and disorders within our mission while, at the same time, help us to keep our ultimate goal in sight. That goal is to improve the quality of life for those afflicted with these diseases, their families, and society, in general.

Opportunities We See

These are exciting times. Opportunities have never been greater for scientific discovery made through basic research--and the ability to adapt and apply those discoveries to clinical settings. The overriding objective of our Strategic Plan, therefore, is to take full advantage of the opportunities at hand for the benefit of human health.

The NIDDK's Strategic Plan acknowledges and incorporates into its objectives the revolution in biomedical research that is being spurred by a wave of new and improved technologies:

• Gene discovery and genetics research are opening the way to impressive new approaches in the diagnosis, treatment and prevention of disease.
• Breakthroughs in basic cell biology are helping to unravel the complexity of living systems by identifying the impact that subtle molecular changes have on cells and tissues.
• Advances made through epidemiology and clinical investigation are making it possible to identify risk factors for the occurrence and progression of disease, which in turn is stimulating new research directions and therapeutic approaches.

Challenges We Face

At the same time that our Strategic Plan identifies opportunities, it also addresses the challenges that need to be overcome in order to achieve those objectives. Foremost among these challenges, and a theme that runs throughout the plan, is the need for improved research infrastructure and capacity, including the need to attract and retain talented researchers, recruit more volunteers to participate in the evaluation of new disease treatments, increase the number of model systems for our studies, and make data more accessible to a wider range of investigators through the use of new medical imaging and bioinformatics technologies.

Also, to enhance the mobilization and leveraging of resources to fight disease, the NIDDK is taking a leadership role in trans-NIH initiatives, and we believe that the cross-cutting scientific themes in our Strategic Plan will help to spur this effort as well. In October 1999, 26 speakers representing voluntary and professional health organizations concerned about diseases within the NIDDK's research mission endorsed and commended NIDDK for the cross-cutting scientific approach and conceptual framework of our plan.

The Course We Are Charting

In addition to our Strategic Plan, this document also includes an overview of the magnitude of the challenges posed by the diseases within the NIDDK's mission, a summary of many of the ongoing programs and mechanisms supported by the NIDDK, examples of the relevance of cross-cutting scientific research to disease, and an overview of the process that resulted in our Strategic Plan.

It is our hope that, as you read through this document, you will gain a deeper understanding of the NIDDK's structure and mission, as well as the course our Strategic Plan is helping us to chart so that we can capitalize fully and productively on this era of unprecedented scientific discovery.

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About the NIDDK

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is the fifth largest among the institutes that the National Institutes of Health (NIH) comprise. The NIDDK conducts and supports a broad range of fundamental and clinical sciences related to programs in numerous diseases affecting the public health, including diabetes, endocrinology, and metabolic diseases; kidney, urologic and blood diseases; and digestive diseases and nutrition. The economic burden to society of these diseases is estimated to exceed $300 billion annually.

The NIDDK also maintains a strong commitment to research training and research career development, with a special emphasis on the physician-scientist, as well as our recruiting and retaining under-represented minorities and women in biomedical research careers.

Because of its broad mission, the NIDDK interacts with more than 100 voluntary health and professional organizations with a special interest in the Institute's programs.

Divisions That NIDDK Comprises

The NIDDK is composed of four scientific operating divisions and one administrative division.

The Division of Diabetes, Endocrinology, and Metabolic Diseases is responsible for extramural research and research training related to diabetes mellitus; endocrinology, including hormone and growth factors important in osteoporosis and breast and prostate disease; and metabolic diseases, including cystic fibrosis.

The Division of Digestive Diseases and Nutrition is responsible for managing research programs and research training related to liver and biliary diseases; pancreatic diseases; gastrointestinal diseases, including motility, immunology, and digestion in the gastrointestinal tract; nutrient metabolism; obesity; eating disorders; and energy regulation.

The Division of Kidney, Urologic, and Hematologic Diseases supports research and research training related to the physiology, pathophysiology, and diseases of the kidney, genitourinary tract, and the blood-forming organs to improve or develop preventive, diagnostic, and treatment methods.

The Division of Intramural Research conducts research and training within the Institute's laboratories and clinical facilities in Bethesda, Maryland, and Phoenix, Arizona. The hallmarks of the NIDDK Intramural program are excellence in scientific productivity and diversity. The research conducted by this division spans the breadth of biomedical investigation, from basic science to clinical studies.

In addition, NIDDK scientific divisions support a variety of trans-NIDDK and trans-NIH career development and training awards.

The Division of Extramural Activities, an administrative division, is responsible for issues related to grant and contract administration and review.

Cross-Cutting Programs

The NIDDK is a strong supporter of research that spans the division lines, such as studies of diabetes and obesity. The NIDDK's scientific operating divisions and programs are linked by a shared interest in the biochemical and genetic processes underlying disease. Close communication among the NIDDK, other NIH institutes, voluntary and professional organizations with an interest in the diseases within the NIDDK's research mission, and related Federal agencies help to mobilize and leverage the resources in these vital areas of scientific investigation.

Budget Allocations

The majority of the NIDDK's budget supports investigator-initiated research grants. During FY 1999, for example, the NIDDK funded 2,653 research grants; 65 research centers; 249 career and other research awards; 926 research training slots; 68 research and development contracts; and 20 intramural laboratories and branches. This type of research investment enables the Institute to maintain a high degree of budget flexibility so as to take full advantage of newly emerging scientific opportunities and apply them to the various needs of its programs and divisions.

To ensure high scientific standards among NIDDK-funded projects, all grant applications, whether initiated by a researcher or solicited by the NIH, are evaluated through a two-step peer review process, mandated by law. That is, all applications are first assessed for their scientific and technical merit by a group of non-Federal expert scientists. Applications are then reviewed for program relevance by the NIDDK National Advisory Council, comprising a group of eminent scientists and lay individuals.

In FY 1999, the NIDDK invested 70% of its $994 million budget in investigator-initiated research. About 8% of the NIDDK's FY 1999 grant budget was allocated for clinical trials that support testing of various methods of therapy and/or prevention in disease areas; approximately 4% went for Merit Awards to support the work of distinctly superior researchers identified by the NIDDK National Advisory Council; and about 8% was in program project grants for the support of broadly based, multidisciplinary research programs that have specific major objectives.

As mandated by law, 2.65% of the NIDDK's grant budget was in the Small Business Innovation Research Program, a mechanism that allows the government to enter into partnerships with small companies.

In addition to supporting research grants proposed by investigators, the NIDDK issues research solicitations in the form of Program Announcements (PAs), Requests for Applications (RFAs) and Requests for Proposals (RFPs) to stimulate scientific investigations in specific areas. These solicitations are typically issued to capitalize on compelling new research findings, and to stimulate research activities in vital areas of programmatic importance. The NIDDK also leads the development of, or participates actively in, trans-NIH research solicitations.

The NIDDK sponsors a wide range of scientific conferences and workshops, ad hoc program planning meetings, and other efforts to secure external scientific advice and public input into the development of its grant research portfolio, as well as to recruit new research talent into specific fields of study. The Institute also encourages both new and experienced investigators in related disciplines to expand their efforts to other disciplines.

The 30% of the NIDDK's FY 1999 budget that is not directed to investigator-initiated research grants was allocated as follows: 5.5% for research centers; 3.3% for research careers and other research; 3.7% for research training; 3% for research and development contracts; 10.6% for intramural research; and 2.6% for research management and support, i.e. administrative costs.

Programs to Enhance the Health of Minorities and Women

The NIDDK participates in a number of programs targeted to under-represented minorities in biomedical research. Included among these programs is the NIH Minority Supplement Program that supports minority group members from secondary schools through to new investigator status. Another program provides additional positions on training programs for minorities, principally at the postdoctoral level.

The Institute also awards "re-entry" supplements to research grants to support women who have completed their research training but have had to leave research for a period of time, generally because of family obligations.

With respect to minority health issues, the NIDDK and the Office of Research on Minority Health have developed an effective and synergistic partnership over the last few years. By working together, we have established several major collaborations that assist minority researchers and benefit research on diseases and disorders within our mission that disproportionately affect minority populations. We also are working on concepts to enhance clinical research in minority populations and at minority research institutions.

In addition, the research programs of the NIDDK are dedicated to studying chronic diseases of direct relevance to women's health and also has a strong and synergistic partnership with the Office of Research on Women's Health. The NIDDK is committed to closing the gaps in understanding disease processes that pose a special problem for women and to developing effective preventive and therapeutic measures in these disease areas.

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Magnitude of the Challenges Facing the NIDDK

The diseases within the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK's) research mission cut across the entire range of internal medicine and related areas of medical practice, and are models of the complex interaction of genetic, autoimmune, neuroendocrine, metabolic, and other mechanisms of disease. Collectively, these diseases affect virtually every part of the body, from the level of the cell, to organ systems, to the interactions of the human body as a whole. They all seriously diminish the quality of life of those afflicted, their families, and loved ones. In addition, the health care costs of the diseases represented in NIDDK-supported research are significantly large segments of the total national burden of disease, estimated at $1 trillion a year by HCFA.

Documented statistics show, for example, that more than half of the entire U.S. population is affected by one or more of the diseases within the NIDDK's research mission, and, according to the Health Care Financing Administration (HCFA), these diseases consume up to 30% of the nation's health care costs paid by Medicare.

These numbers are staggering in terms of human life diminished or lost and dollars spent. However, even these numbers may not reflect the true impact of these diseases. For example, the death of a diabetic patient with cardiovascular disease is traditionally recorded as a cardiovascular death, even though diabetes may have been the root cause of the individual's cardiovascular condition and resultant death.

The magnitude of the challenges facing the NIDDK is demonstrated by the following disease areas for which there are documented statistics. Keep in mind that the information below does not take into account the hundreds of conditions related to these major disease areas for which no reliable data are available.

Endocrine and Metabolic Diseases

Most common among these types of diseases are diabetes and obesity. Both type 2 diabetes and obesity, for example, involve resistance to insulin action, which results in an increase in blood lipids (especially low density lipoprotein and triglycerides) leading to atherosclerosis, as well as certain defects in cellular signaling. Kidney disease of diabetes (KDDM), a chronic and disabling complication of diabetes, is the most common cause of end-stage renal disease and a perfect example of how certain diseases span the mission of the NIDDK. Osteoporosis (a condition that results in loss of bone density) is a severe problem for post-menopausal women while benign prostatic hypertrophy, more commonly referred to as enlargement of the prostate, affects a high percentage of men older than 60.

Diabetes

• Affects 16 million people in the U.S.
• 800,000 new cases each year.
• Leading cause of new blindness, end-stage renal disease, and non-traumatic leg amputations.
• Major risk factor for heart disease, stroke, and birth defects.
• Leading cause of death in people with diabetes is coronary heart disease.
• Leads to higher death rates from pneumonia, influenza, and many other illnesses.
• Affects all segments of the population, but manifests highest incidence in non-Hispanic African Americans, Mexican Americans, other Latin Americans, Native Americans and Alaskan Natives, as well as in Asian Americans and Pacific Islanders.
• Cost to nation: More than $98 billion annually, including direct and indirect costs (i.e. disability, work loss, and premature death).
• Shortens average life expectancy by up to 15 years.

Obesity

• Affects 60 million people in the U.S. (25% of all women; 20% of all men; 37% of all minority women).
• Associated with greatly increased risk of complications similar to those in type 2 diabetes, including cardiovascular problems, higher levels of harmful lipids in the blood, and increased mortality, as well as other complications more specific to obesity such as hypertension; certain cancers; arthritis in the hips, lower back and legs; gout; and gallbladder disease.
• Increasing in prevalence among children.
• Cost to nation: More than $99 billion annually in both direct and indirect costs.

Kidney Disease of Diabetes (KDDM)

• Most common cause of end-stage renal disease (ESRD).
• Each year, more than 50,000 people are diagnosed with ESRD caused by KDDM.
• ESRD, like diabetes and obesity, is most prevalent in African Americans and Native Americans.
• High blood pressure, as well as high blood sugar levels increase the risk that a person with diabetes will progress to ESRD.
• Each year, nearly 200,000 Americans undergo dialysis while more than 12,000 receive kidney transplants.
• Cost to the nation: More than $15.64 billion annually, more than $10 billion of which comes in the form of Medicare expenditures.

Osteoporosis

• Severe problem for post-menopausal women and older men.
• Responsible for more than 15 million fractures annually, including hip, vertebrae, and wrist fractures.
• These fractures are a major cause of disability, hospitalization, and loss of independence, especially for people over the age of 50.
• Cost to the nation: Direct costs of medical care alone are about $13 billion annually.

Benign Prostatic Hypertrophy (BPH)

• More than half of all men in their sixties, and as many as 90% in their seventies and eighties, have symptoms of BPH, commonly known as enlargement of the prostate gland.
• Can lead to incontinence, infections, stones, and kidney damage.
• BPH results in about 375,000 hospital stays each year.
• Although there is no evidence that BPH itself increases the chances of getting prostate cancer, approximately 30,000 of the 120,000 men each year diagnosed with prostate cancer die of the disease.

Autoimmune Diseases

An important class of illness is autoimmune diseases, in which antibodies develop against one's own tissues and harm the affected organ system. There are many autoimmune diseases for which the NIDDK has research responsibility. These include: type 1 diabetes; autoimmune thyroiditis; hyperthyroidism; other autoimmune endocrine syndromes (including primary adrenocortical insufficiency); autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; chronic gastritis; inflammatory bowel disease; glomerulonephritis; lupus nephritis; and aplastic and hemolytic anemias.

What follows are documented statistics on two of the more prevalent autoimmune diseases within the NIDDK research mission:

Type 1 Diabetes

• Involves a genetic predisposition and usually begins in childhood.
• Gradually destroys the pancreatic insulin-secreting cells (beta cells), which leads to life-long dependence on insulin to survive.
• Affects approximately 750,000 to one million Americans, or 5% to 10% of the 10.3 million people with diagnosed diabetes.
• Complications as a result of type 1 diabetes are essentially the same as described earlier.

Inflammatory Bowel Disease

• Affects approximately 500,000 Americans each year.
• Results in more than 100,000 doctor visits annually, most of which (two-thirds) are related to Crohn's Disease, a disorder affecting primarily the small intestines.

Genetic Diseases

Diabetes and obesity, discussed above, are now being studied for causative genes along with a host of other disorders, including several hundred disorders resulting from inborn errors of metabolism. Now that genes are being identified in many conditions not traditionally thought of as genetic, the phrase "genetic diseases" has evolved into a much broader definition than just "inherited diseases" present from birth. We know, for example, genetic mutations can cause diseases often precipitated by environmental triggers. While exacting a heavy toll on those affected, the overwhelming majority of these genetic disorders are not common enough to have extensive statistics on their burden of illness. Cystic fibrosis and polycystic kidney disease (PKD), however, are exceptions.

Cystic Fibrosis (CF)

• One of the most prevalent and tragic genetic diseases of the young. Approximately 1,000 new cases are diagnosed each year, usually before 3 years of age.
• Characterized by changes in the functioning of many exocrine organs as well as excessive production of thick, sticky mucus in the airways.
• Major gene associated with CF was found in 1989, with subsequent discovery of protein it produces.
• An individual must inherit two copies of the defective gene--one from each parent--to acquire the disease. An estimated 8 million people carry a single copy of the defective gene.
• With improved treatment, CF no longer means death in early childhood; as a chronic disease, it allows patients to live into their 30s or 40s.
• Most adult CF patients eventually succumb to lung infections and respiratory failure.

Polycystic Kidney Disease (PKD)

• Genetic-based disease that results in the development of numerous cysts in the kidney, liver, and other organs.
• Cysts slowly replace much of the kidney, thereby reducing kidney function, often leading to kidney failure.
• Causes infections, hematuria, stones, high blood pressure, and other problems.
• Affects 500,000 Americans and is the fourth leading cause of kidney failure.

Chronic Infections and Inflammatory Diseases

Viral and bacterial infections not treated or eliminated in the acute stage go on to produce chronic diseases, such as hepatitis, nephritis, gastritis (and non-ulcer dyspepsia), pancreatitis, and others. The impact of such conditions on health and human suffering is sizeable.

Hepatitis C (HCV)

• The most common blood-borne infection in the U.S. and a major cause of end-stage liver disease.
• An estimated 4 million Americans are infected with HCV, although most do not know they carry the virus.
• 85% of those infected become chronic carriers; about 20% develop cirrhosis, some of whom develop liver cancer.
• Leading cause of liver transplants.
• Causes 8,000 to 10,000 deaths annually. The number is expected to triple in the next 10 to 20 years.
• Cost to the nation: Approximately $6 billion annually.

Liver Disease

• Chronic liver disease and cirrhosis affect about 400,000 people annually.
• Each year, chronic liver failure results in an estimated 1 million doctor visits, 300,000 hospitalizations, more than 100,000 newly disabled people, approximately 3,300 liver transplants and 26,000 deaths.

Food-borne Illnesses and Chronic Infectious Diarrheas

• Nearly 100 million new cases diagnosed each year resulting in several thousand deaths annually.
• Hemolytic uremic syndrome is a particularly serious form of chronic infection in which a bacterial invader (Eschericia coli O157:H7) may cause destruction of red blood cells, resulting in kidney damage.

Peptic Ulcers

• Approximately 5 million new cases diagnosed annually.
• Lead to 3 to 5 million doctor visits and nearly 650,000 hospitalizations each year.
• Bacterial infections (by Helicobacter pylori) appear to cause at least 2.5 million cases annually.

Common Disorders with Multiple Causes

Kidney Stones in Adults

• Most common disorder of the urinary tract. It is estimated that 10% of all people in the U.S. (men more than women) will form a kidney stone at some point in their lives.
• Occurrences have increased over the last two decades.
• Commonly caused by excess calcium excreted in the urine, but also are due to kidney infections, as well as to inherited metabolic abnormalities.
• Result in an estimated 900,000 doctor visits and more than 300,000 hospitalizations annually.
• Cost to the nation: Approximately $1.9 billion annually.

Gallstones

• Affect 1 in 10 Americans (women more than men) and are associated with about 3,000 deaths each year.
• Stones large enough to cause pain require 600,000 hospitalizations and more than 500,000 operations annually.
• Obesity is a strong risk factor for gallstone formation.
• Diets associated with rapid loss of excessive weight also increase the risk of gallstones.

Gastroesophageal Reflux Disease (GERD)

• Affects more than 60 million American adults at least once a month; about 25 million adults suffer daily, as do 25% of pregnant women.
• Major symptoms include heartburn and acid indigestion.

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About the NIDDK Planning Process

The National Institute of Diabetes and Digestive and Kidney Diseases' (NIDDK's) Strategic Plan, as part of the NIH response to recommendations of the Institute of Medicine Study on NIH priority-setting and public input, represents an effort on the part of the NIDDK to identify and address the global challenges and opportunities it faces in the next five years with respect to its research mission. The overall objective of the Plan is to create an environment and strategy within the NIDDK to support and enhance scientific and clinical research leading to scientific advances. The ultimate objective, of course, is to improve the quality of life for those affected by disease, their families, and society, in general.

The strategies outlined in this plan are not the product of the Institute acting on its own. Rather, they reflect input to the NIDDK, working in close collaboration with its National Advisory Council, the scientific community at large, and lay and professional organizations with an interest in the disease areas for which the Institute has research responsibilities.

By design, the NIDDK's Strategic Plan is not a budget or advocacy document. Nor is it disease specific. Instead, the Plan's scientific orientation targets the most promising research the Institute believes is achievable within a five-year time frame, and focuses on long-term, trans-NIDDK and trans-NIH, cross-cutting scientific themes. These themes include: genes and their impact on disease; cell biology; prevention and treatment of disease; and research infrastructure.

The strategies built around the goals and objectives identified through these cross-cutting scientific themes are broadly relevant to a wide range of diseases within the NIDDK research mission.

Scientific Working Groups

The NIDDK's Strategic Plan was developed through a series of scientific working groups, one group for each of the Strategic Plan's four themes (see above). Each working group consisted of 12 or more participants, an NIDDK writing chair, at least one intramural scientist, one lay person, and at least one member from our National Advisory Council. The NIDDK Senior Management served as the writing chairs and helped to cross-fertilize ideas among the working groups.

Working groups were responsible for identifying and emphasizing the common themes, scientific opportunities, and research challenges across the programs and divisions of the NIDDK.

Some key features of the planning process that working groups needed to take into consideration included procuring public involvement and input, and making the Plan understandable to lay audiences so as to foster wide distribution.

A Strategy Built Upon the NIDDK's Annual Program Plan

The cross-cutting themes of the NIDDK's Strategic Plan are designed to help the Institute set a scientific vision to aid in its development of specific initiatives on an annual basis. As such, the Strategic Plan complements and builds upon already existing planning processes within the NIDDK's operating divisions and the Institute as a whole. Insight into the NIDDK's annual program planning process, therefore, will provide a greater understanding of the Institute's five-year Strategic Plan.

The NIDDK Program Plan

Taking into consideration available resources, the NIDDK's annual program planning process helps guide the development and implementation of specific research initiatives for each upcoming fiscal year. It sets a framework for future program activities, as well as for facilitating the efforts of the NIDDK's scientific and lay constituents. Each year, this process culminates in the presentation to, and discussion by, the NIDDK Advisory Council of a planning document called the "NIDDK Program Plan."

The NIDDK Program Plan contains two major components, which are presented to the Advisory Council at different times of the year. The first component is the Research Progress Reviews. These reviews provide examples of recent major areas of scientific accomplishments within the NIDDK research mission and are presented to Council in February.

The second part of the NIDDK Program Plan is the Program Initiative Concepts component, which is basically a "wish list" put forth by the NIDDK's three extramural scientific operating divisions. This component of the Program Plan contains scientific initiative concepts the divisions would like to see implemented if funding is made available. Each concept is based on recommendations of the research community, and the NIDDK advisory groups, or directives from the U.S. Congress and/or the Administration. This component also provides a summary overview of the NIDDK's major ongoing initiatives and is presented to the full NIDDK Advisory Council each September.

Initiatives proposed in the NIDDK Program Plan:

• Build on past accomplishments;
• Reflect emerging scientific needs and opportunities;
• Are responsive to the changing fiscal environment and new Congressional and Administration directives; and
• Are consistent with the NIDDK's commitment to investigator-initiated research.

The Program Plan is actually a compilation of the separate annual planning processes of the NIDDK's three extramural scientific divisions and reflects an effort on the part of each division to identify the best scientific opportunities to pursue.

Annual Planning Process of the NIDDK's Extramural Scientific Operating Divisions

Each of the three extramural divisions employs a range of planning mechanisms, starting at the programmatic staff level.

Program staff assess the state-of-the-science in their respective areas by attending and convening scientific meetings, reviewing their grant portfolios and published literature, and through discussions with grantees and other individuals and organizations within the scientific community.

For example, when areas of scientific opportunities are identified by both the NIDDK and the extramural communities, they are prioritized through discussions held with program staff and their respective division directors. Preliminary program initiatives are then discussed with the division's sub-council of the Institute's National Advisory Council.

Divisions also seek participation from leading professional societies and lay organizations that have an interest in the areas of the division's research portfolio. Input is also solicited from experts in specific areas through specially created ad hoc advisory groups. Workshops are another venue through which the NIDDK extramural divisions seek input into their planning activities. Divisions do not undertake major initiatives without first seeking input and advice from these groups.

Benefits of the NIDDK's Planning Process

In addition to being a requirement of the NIH and an expectation on the part of the U.S. Congress, the NIDDK program planning process:

• Enables the Institute to reply accurately to frequent public and Federal inquiries regarding its programs, i.e. the state of the science in a particular field; examples of recent scientific progress; perceived research needs and opportunities; resource needs and allocations; and the Institute's approaches for meeting its responsibilities.
• Serves as a means to aid Institute staff members in keeping abreast of developments in their areas of responsibility. It is through this expertise that management responsibilities are coordinated.
• Permits the Institute to be in a position to act in a timely manner to implement a given program or to stimulate work in a certain special-emphasis area should the need or opportunity arise and the funds be made available for that purpose.
• Provides material to justify the value of existing scientific activities and to be able to identify compelling scientific needs and opportunities that warrant the allocation of additional resources.

Strengthening the NIDDK's Planning Process

The NIDDK's program planning process is continuously evolving and, as stated previously, is predicated on wide-ranging and continuous collaboration between the NIDDK and non-Federal scientists and other advisors, including the Institute's National Advisory Council and sub-councils, as well as ad hoc advisory groups to the NIDDK operating divisions, NIDDK-sponsored workshops and conferences.

Since 1997, the NIDDK has solicited wider input from the Advisory Council and the broader scientific community in an effort to strengthen its program planning process. Each of the NIDDK extramural operating divisions, for example, is now interacting more fully with its respective communities through a variety of means, ranging from ad hoc meetings to conference calls.

As a result of the interaction and feedback received from the Advisory Council and other external advisors, the approach to the Program Initiative Concepts portion of the Program Plan document has been changed.

Changes already introduced to strengthen the Program Initiative Concepts document include:

• Greater linkage between the Program Initiative Concepts and ongoing initiatives within the NIDDK research portfolio.
• Greater emphasis on the scientific rationale for Concepts and less emphasis on the "instrument" or mechanism through which the scientific need and/or opportunity may be pursued or implemented.
• Linking Concepts to the NIH Director's Areas of Emphasis

In future planning processes linkages will be made between Annual Program Initiative Concepts and the cross-cutting themes of the NIDDK Strategic Plan.

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The National Institute of Diabetes and Digestive and Kidney Diseases' Strategic Plan

The National Institute of Diabetes and Digestive and Kidney Diseases' (NIDDK) Strategic Plan addresses the global challenges and opportunities facing the NIDDK, and outlines research directions within the Institute's mission that be should pursued over the next five years. The Plan represents a collaborative effort, with input coming from NIDDK's senior scientific management working with the National Advisory Council, the scientific community at large, lay and professional organizations, and the public.

During 1999, NIDDK senior management held multiple Working Group meetings, had discussions with Working Group members, analyzed the existing NIDDK research portfolio, solicited comments from lay and professional organizations, and heard public comment. During the development of the Plan, Working Groups interacted closely with one another to cross-fertilize ideas among themselves. They also evaluated current state-of-the-art science in an effort to develop a comprehensive and scientifically achievable plan.

Working Groups were responsible for identifying and emphasizing the common, scientific, cross-cutting themes, scientific opportunities, and research gaps and challenges across the programs and divisions of the NIDDK. In order to adequately reflect the compelling scientific opportunities and public health needs identified through this deliberative process, the Plan has been divided into the following four sections or themes:

• Genes and Disease
• From the Cell to the Organism: Unraveling the Complexity of Living Systems
• Prevention and Treatment of Disease: Epidemiology and Clinical Investigation
• Research Infrastructure

These themes were presented to and broadly endorsed by the NIDDK's National Advisory Council, the NIDDK research community and the many lay and professional organizations with an interest in the research conducted and supported by the NIDDK.

In the sections that follow, each Working Group presents background information related to its respective theme, and sets forth a series of objectives; insights related to those objectives; and a series of implementation strategies for achieving those objectives.

Working groups made every effort to articulate their portion of the Plan in non-technical language that would be understandable to a broad public audience. However, given the intensely science-oriented nature of the research conducted and supported by the Institute, the Plan does contain some scientific terminology. Therefore, a glossary of scientific terms and acronyms has been appended.

A summary of the broad and overarching goals, objectives and strategies of the Institute over the next five years is as follows:

• To promote the health of the American public through scientifically meritorious basic and clinical biomedical and behavioral efforts and related programs.

• To develop a sound base of fundamental science on which future clinical research advances can be built.

• To understand the natural history and processes of diseases and disorders within the NIDDK mission.

• To gain insight into, and develop more effective treatment and prevention strategies for, diseases and disorders that disproportionally affect ethnic groups and other special populations, such as women and children, so that these health disparities can be reduced or eliminated.

• To develop effective treatments for the diseases and disorders within the NIDDK mission and strategies for preventing or delaying their onset.

• To develop effective means of preventing, delaying or ameliorating the complications of the diseases and disorders within the NIDDK mission.

• To develop and apply technologies, innovative research techniques and methods from which will flow future basic and clinical research advances and improvements in the health of all Americans.

• To facilitate the continuation of an adequate cadre of basic and clinical biomedical research investigators through the recruitment and retention of talented individuals to research training and research career development programs, with special attention to minority recruitment and retention programs.

• To promote dissemination and application of research results emanating from the NIDDK basic and clinical research studies, through outreach programs, education programs, and other means, in ways that are culturally appropriate and meaningful to target audiences.

 

GENES AND DISEASE

Overall Goal: To strengthen our understanding of the role of genes in disease in order to improve prevention and treatment, and ultimately to cure the diseases for which NIDDK has research responsibility.

BACKGROUND

Opportunities and Challenges

Why Emphasize Genes?

Over the next 5 years, NIDDK's mission--to improve understanding and ultimately to find better ways to prevent, treat and cure diseases in its areas of responsibility--will be achieved in part through intensified study of genes and disease. A major driving force behind the dramatic scientific opportunities of the next decade, therefore, will be the information emerging from the Human Genome Project. Even now, scientists regularly discuss the imminent arrival of the "post-genomic era," recognizing that within 2 or 3 years, as the sequence of the entire human genome becomes known, we will face great opportunities and new challenges.

These opportunities and challenges include:

Determining How Gene Defects Relate to Inherited Diseases

Many diseases "run in families," and every physician knows that family history tells much about the risk of disease. Understanding how diseases are inherited and identifying the specific gene or genes that confer susceptibility are critical to understanding the diseases and, ultimately, improving prevention and treatment.

Some familial diseases have the relatively simple and predictable patterns of Mendelian inheritance, named after Gregor Mendel, the Austrian monk who first described them. We also call these diseases monogenic, reflecting the fact that, by and large, they are caused by a defect in a single gene.

The last decade has seen breathtaking progress in identifying underlying defects in monogenic diseases. In virtually every case, identification of the genetic defect has intensified research of the disorder and increased understanding of the mechanisms of disease. These cascading events are spawning new diagnostic tests, earlier diagnosis and, in many cases, new therapeutic strategies.

Some familial diseases are quite rare, and sometimes the identified genetic defects are responsible for only a small portion of cases. But the known defects provide important clues for all cases. With the availability of the complete sequence of the human genome, identifying the genes responsible for monogenic disorders will become faster and easier.

A second category of familial diseases are polygenic, also sometimes called "complex traits." Many serious and very common diseases run in families, but the inheritance pattern suggests that they result from interactions of several genes, not from a single defect.

Compared to monogenic diseases, identifying defective genes in polygenic disorders has proven much more difficult. Genes involved in a few polygenic disorders have been identified, but by-and-large, this is an area of research that is just beginning. The complete sequence of the human genome will permit new approaches to understanding polygenic diseases.

Understanding Gene Function

After identifying a faulty gene, the next--and absolutely critical--step is to understand the gene function, that is, how the gene works and how defects in it lead to disease. Modern methods have revolutionized the process of studying gene function, and investigators have clarified how mutations disturb the function of many disease genes. Nevertheless, enormous scientific hurdles remain. Strategies to strengthen studies of gene function are also a major focus of all parts of this Strategic Plan.

Determining How Environments Affect Genes

Inheriting a specific gene, alone, does not necessarily mean an individual will develop a disease. In fact, most chronic diseases result from interactions among genes, life-style, and environment. Thus, diet, exercise, stress, and many other environmental factors influence whether an individual gets a disease and how severe it will be. But, because genes determine how we respond to diet, environmental toxins, drugs, and stresses of daily life, what we learn about genes may also help us deal with these other factors.

Understanding the interplay of these factors--and how people vary in their responses--may teach us how to promote health better and, potentially, predict who will be vulnerable to drug side-effects and who will benefit from diet and other life-style changes.

Understanding How Modifying Genes Affects Disease

Genes do not act alone. Even the "same" genetic disease can manifest itself differently. For example, some very young children with cystic fibrosis have a massively debilitating disease, while others--even those with the same mutation--may be relatively free of symptoms until late adolescence or early adulthood. Similarly, polycystic kidney disease may result in early kidney failure in one family member and no apparent kidney problems in another family member. This variability suggests that the product of other genes may alter the function of the primary disease gene; in some instances, for example, one gene product may be able to substitute for another. Knowing more about these modifying genes and how they effect disease has enormous promise as a way to identify new approaches to therapy.

Understanding How Genes Determine the Development of Cells and Organs

By identifying and understanding genes that control the formation of healthy specialized cells and organs, we may better understand what errors lead to disease. Disease processes, even late in life, often cause reactivation of genetic programs that participated in early development and organ formation. Genes determine which cells have the potential to continue to divide and allow regeneration of organs. We will be better able to harness the body's capacity to regenerate and heal when we better understand normal development.

Focusing on Strategies to Exploit Genomic Information

Understanding genes, their function, their role in disease and tissue injury, exploiting information about genes to find new diagnostic methods and new therapies are themes that recur in all parts of the NIDDK's Strategic Planning Processes. The focus of this crosscutting theme--Genes and Disease--focuses particularly on the approaches to inherited diseases and on strategies to exploit genomic information to yield critical understanding.

OBJECTIVES

Because genes are important for all aspects of the NIDDK's investigative portfolio, the Working Group on Genes and Disease emphasized genetic diseases and genetic investigation, as well as approaches to disease that rely on systematic application of genomic information.

In formulating the following objectives, the Working Group chose priority areas that cut across the Institute's disease interest areas. These objectives are not intended to be all inclusive, and it is recognized that many important and relevant research projects will fall outside these priority areas.

A. INHERITED DISEASES

A1. OBJECTIVE: Identify the genetic loci and the underlying genes that are responsible for the principal diseases in the NIDDK portfolio, which show familial patterns of susceptibility, both monogenic and polygenic.

INSIGHT: The last decade has seen breathtaking progress in the understanding of monogenic disorders. Many of the diseases caused by a mutation at a single genetic locus are now characterized at a molecular level. Progress in understanding the complex (or polygenic) diseases has been much slower, and will be a key challenge for the next decade.

A2. OBJECTIVE: Identify genetic loci that explain the variable clinical presentation of certain key monogenic diseases and begin to clarify how the interaction of several genetic loci can produce polygenic diseases.

INSIGHT: As discussed previously, a number of genetic diseases are highly variable in their presentation. Environmental factors may explain part of this variability. However, work in animal models, particularly mouse models, has established that secondary modifying genes can alter the expression of a disease gene or substitute for its function. In polygenic disorders the interaction of two disease loci may operate in a similar fashion to that between the primary gene which causes a monogenic disorder and a modifying locus. Identification of such modifying genes, both in animal models and in human disease, is a valuable approach to finding new therapeutic approaches to diseases and understanding gene interactions.

A3. OBJECTIVE: Improve the precision with which we can characterize the clinical phenotype of the key diseases in our portfolio, with the goal of identification of genetically homogenous sub-groups.

INSIGHT: Many of the important complex disorders in areas of NIDDK interest are extremely heterogenous. Current classification schemes and diagnostic categories often do not adequately address this heterogeneity. Systematic collection of patient information and a new generation of clinical tools--including new molecular methods--may in some cases lead to recognition of homogeneous sub-groups, sharing genetic predeterminants. This more precise characterization is expected to speed genetic investigation.

The informed physician-scientist will be critical for this process. The Genes and Disease Working Group emphasized the important role of strengthening clinical investigation for the new scientific opportunities.

A4. OBJECTIVE: For certain key diseases of concern to NIDDK, clarify the extent of familial aggregation.

INSIGHT: For a number of important diseases the extent of familial aggregation is still unclear. Careful studies to establish the relative risk to family members of patients with these disorders is an important step in determining whether or not genetic approaches will be helpful.

A5. OBJECTIVE: Identify the genetic differences that contribute to population differences in susceptibility to disease.

INSIGHT: In many cases, the disproportionate burden of disease experienced by ethnic or racial sub-groups in the population can be explained by genetic differences. These differences may ultimately identify therapies of special efficacy in such sub-groups.

A6. OBJECTIVE: Understand the genetic basis of variable responses to important categories of therapeutic drugs, including genes that result in susceptibility to drug toxicity.

INSIGHT: Some therapies are very effective for some individuals and are virtually totally ineffective for others. The ultimate goal of tailoring the right therapy to each patient will be fostered by intensified study of the role of genetic variability in determining the response to therapeutic drugs and the vulnerability to drug toxicity.

B. GENE PROFILES ALTERED BY DISEASE

B1. OBJECTIVE: Establish for selected major diseases in the Institute's portfolio the patterns of altered gene expression in important target tissues.

INSIGHT: Part of the study of genes and disease needs to include defining the effects of key diseases on the pattern of genes expressed in damaged tissues. Gene expression profiles have special promise for a number of reasons. They are likely to: assist in identification of new therapeutic targets; define candidate genes for studies of complex traits; and provide new tools for diagnosis and management. (NOTE: These methods are discussed further in the following section on strategies to meet our objectives.)

B2. OBJECTIVE: Exploit the potential of gene profiling and other molecular methods to improve methods for disease identification, classification, and determination of prognosis.

INSIGHT: Currently, most diagnostic methods use radiographic tests, biochemical methods or microscopic study of pathological tissue. The methods of molecular biology and new understanding of the role of genes in disease are, however, opening up a range of new diagnostic methods. It will be important to ensure that the potential of these new methods is fully exploited for diseases within the NIDDK mission.

C. GENE PATHWAYS IN ORGAN DEVELOPMENT

C1. OBJECTIVE: Identify the genetic pathways critical for the formation of organs in the NIDDK areas of research responsibility, and understand how these genes work to dictate cell lineage specification.

INSIGHT: Developmental pathways are often reactivated by tissue injury, and regeneration and healing may use the same genes that are active when an organ forms. Strengthening Institute programs in organogenesis, with particular focus on understanding gene pathways that dictate cell lineage, is considered an important objective for ultimately harnessing the potential of these pathways.

C2. OBJECTIVE: Use knowledge of these gene pathways to develop strategies to facilitate healing and regenerative processes and the maintenance and differentiation of stem cell populations.

INSIGHT: Practical implications of intensified study of developmental biology include new strategies for cell and tissue engineering, as well as potential identification of new target molecules for therapeutic intervention.

D. GENE FUNCTION AND REGULATION

D1. OBJECTIVE: Foster investigation that will clarify molecular function of key disease genes.

INSIGHT: A number of the objectives developed in this chapter focus on the identification of disease genes. It is important to reiterate that identification of a disease-causing gene is just a beginning that needs to be followed by intensified study of disease mechanism. (NOTE: Subsequent sections in this Strategic Plan include discussion of functional studies of genes at the cell and organ levels, and studies of how genes participate in the injury process.)

D2. OBJECTIVE: Foster investigation that will clarify fundamental mechanisms of gene regulation by hormonal, dietary and environmental variables.

INSIGHT: Study of regulation of gene expression is a key area of strength in our investigative portfolio. Elaborate networks of interacting proteins, the complexity of which is just beginning to be understood, regulate gene expression in the cell nucleus. Many new scientific opportunities exist to untangle these regulatory mechanisms. Intensified study of the regulation of gene expression is anticipated to yield new understanding and ultimately to identify new therapies.

IMPLEMENTATION STRATEGIES

Progress toward each of the objectives defined above will most likely result from the collective achievement of a number of individual investigative teams supported by the NIDDK's scientific research portfolio that consists of investigator-initiated grants. The strategy of funding such grants and making them the core of the Institute's scientific research portfolio has been highly successful in the past and should continue.

However, in the process of developing its portion of the NIDDK's Strategic Plan, the Working Group on Genes and Disease identified a number of barriers that can limit the capacity of the individual investigator to make progress toward these objectives.

The proposed implementation strategies that follow recognize these barriers. Subsequently, a number of the strategies recommend investment in the development of research resources and research tools that will enhance the ability of the individual investigator-led teams to achieve their objectives.

(NOTE: Discussion of implementation strategies did not attempt to determine the best mechanism for the NIDDK to encourage each type of effort. It was recognized that in some instances specific and targeted research solicitations would be appropriate, and in others educational efforts such as workshops might be the most effective response.)

A. STRATEGIES TO STRENGTHEN GENETIC STUDIES

The Working Group on Genes and Disease felt the process of identifying the genetic defects responsible for monogenic disorders has substantial momentum and current strategies were viewed as having a track record of success. Vigorous continued support for such efforts was enthusiastically recommended.

The Working Group also identified a number of barriers to identification of the genes responsible for polygenic or complex traits, the most notable being the major scientific difficulty of the undertaking. Investigators studying polygenic disorders uniformly face resource limitations, particularly because of the need for large cohorts of patients, and the costs and difficulty of good clinical phenotype characterization.

Because of the substantial difficulty and costs of studying polygenic disorders, the Working Group strongly advised that efforts in this area need to be carefully targeted. Priority setting should weigh the public health burden of the disease in question, the extent to which familial aggregation is clear-cut, and the likelihood of identification of functionally important genetic pathways.

Implementation strategies to strengthen genetic studies are as follows:

A1. STRATEGY: Facilitate the development of cooperative consortia in order to permit large-scale genetic studies, particularly for polygenic disorders. Create innovative models for cooperative consortia, in which the advantages of cooperation are secured, but innovative approaches, particularly for phenotype characterization, are not discouraged.

A2. STRATEGY: Exploit fully homogeneous populations and patient sub-groups with monogenic inheritance patterns to reduce genetic complexity.

A3. STRATEGY: Develop methods to strengthen patient recruitment into genetic studies and to improve public awareness of the potential benefits of genetic research.

A4. STRATEGY: Encourage development of innovative analytic strategies for genetic studies.

A5. STRATEGY: Generate clear expectations for patient data and DNA sharing in all NIH-funded genetic studies.

A6. STRATEGY: Encourage research that will improve the precision of phenotypic characterization with the goal of identification of genetically homogenous sub-groups. Strengthen population-based studies of certain key NIDDK diseases to improve definition of natural history and its variability.

B. STRATEGIES FOR SYSTEMATIC ASSESSMENT OF GENETIC INFORMATION

One important strategy to exploit information emerging from the Human Genome Project is to undertake systematic studies of patterns of gene expression. The rapidly evolving technology for gene profiling currently permits assessment of the expression profiles for large numbers of genes in cultured cells and organs, and it may soon be feasible to assess gene expression at the level of a single cell or a few cells. Also under development are methods to assess gene expression systematically at the protein level.

The techniques show substantial promise to open unexplored and unanticipated avenues for research. Applied to diseased tissue, gene expression profiles can identify candidate genes for genetic studies and target molecules for therapeutic intervention. Applied to sequences for which the gene function is still unknown, these methods can identify important new genes and provide important clues to gene function. Used to study gene transcription, the methods can establish groups of genes that show coordinate regulation.

The Working Group on Genes and Disease considered it important to encourage promising applications of these methods and to make the information from these techniques broadly available.

Implementation strategies for systematic assessment of genetic information are as follows:

B1. STRATEGY: Use systematic studies of gene expression in diseased human tissue from patients with polygenic disorders to identify candidate loci.

B2. STRATEGY: Use systematic studies of gene expression to characterize stem cell populations and cell lineage specification.

B3. STRATEGY: Characterize animal models of disease and determine the extent to which gene profiles mimic human disease.

B4. STRATEGY: Ensure--in cooperation with trans-NIH efforts--investment in technology development for systematic gene expression studies.

B5. STRATEGY: Ensure ready availability of methods and reagents to NIDDK investigative communities.

C. STRATEGIES FOR DEVELOPING GENETIC MODELS TO STUDY DISEASE

Deciphering the human genome will require a wide range of biological models and systems, and matching the scientific question to the right model will be of critical importance. Good choice of animal models and other model systems can have substantial impact on the rate of progress in studying disease.

Many fundamental biological processes show extensive evolutionary conservation, and there are a number of striking examples where findings from simpler organisms, such a C. elegans, fruit fly, yeast and zebrafish, have yielded immediately relevant insights into human disease.

The mouse is emerging as a model for human disease of particular importance, in part because it is the mammalian model in which both genetic studies and genome manipulation are most advanced.

Implementation strategies strengthen studies of genes and disease in animal models are as follows:

C1. STRATEGY: Encourage the development of animal models that more faithfully replicate human disease processes.

C2. STRATEGY: Use systematic gene expression profiling to establish relevance of animal models to human disease.

C3. STRATEGY: Encourage the exploitation of a wider range of model organisms.

C4. STRATEGY: Participate in the development of genomic and genetic tools for model organisms of particular promise for the NIDDK areas of science.

C5. STRATEGY: Develop shared molecular tools and reagents for model organisms important for study of the genetics of disease.

D. STRATEGIES FOR THE EFFECTIVE USE OF INFORMATION TOOLS

It is widely recognized that the provision of certain kinds of easily accessible, searchable information is dramatically changing the process of science. The Working Group on Genes and Disease felt that informatics needed for each investigative community varied substantially, and that activities in this area needed to be carefully tailored to scientific need, and well-coordinated with other trans-NIH efforts.

Implementation strategies for the effective use of information tools are as follows:

D1. STRATEGY: Develop programs to improve availability of organ-specific annotated sequence information.

D2. STRATEGY: Develop appropriate informatics tools and databases for study of the genetic basis of disease.

D3. STRATEGY: Ensure that investigative communities have access to training in the use of informatics tools.

FROM THE CELL TO THE ORGANISM: UNRAVELING THE COMPLEXITY OF LIVING SYSTEMS

Overall Goal: To understand the internal workings of each cell type in isolation, how cells function in the communities that make up tissues and organs, and how cell function is integrated in the intact human body so as to better prevent, treat and cure diseases.

BACKGROUND

The Importance of Studying Cells

To repair and maintain a car a mechanic must understand the function of each part of the vehicle, how each part connects to form a system such as the engine, brakes or steering, and how these systems work together to allow the car to operate. Similarly to prevent, treat and cure disease, we must understand the make-up, function and interactions of living cells, tissues and organ systems.

To understand when and how cells are harmed in the course of disease, we must first understand how healthy cells function and communicate with each other at the molecular level. Such knowledge is essential to our ability to identify subtle but crucial molecular changes in cells and tissues. This knowledge also has implications for early detection of disease, prediction of disease course, response to particular therapies, and identification of molecular targets for development of new therapies.

All cells share common features

Human cells are composed of the same substances (proteins, fats, carbohydrates, nucleic acids, salts and water) that are found in all living cells. Many of the more complex molecules within cells, such as genes and the proteins they encode, occur in what is often referred to as families, with each protein or gene having a similar but not identical genetic sequence.

Human cells may contain many members of each family, often with overlapping functions. This complexity can make it difficult to tease out the function of individual molecules. Often clarification of the function of these molecules is easier in simpler organisms, such as yeast, worms or flies, which generally share at least one member of each family of proteins found in humans but contain fewer such family members.

As a consequence of the fundamental similarities in mechanisms by which all cells operate, keys to understanding function, such as digestive or kidney function, and diseases such as diabetes, or liver disease may lie in research in these simpler systems. These connections between humans and lower life forms must be recognized and exploited through study of simpler "model organisms" that are directly relevant to human cells.

Major differences among cell types

Despite the similarities common to all life forms and the principles underlying cell function, cells vary greatly in size, shape and function. In each person a single cell, the fertilized egg, gives rise to hundreds of different cell types. Each cell in the body contains the same set of genes. If it can be determined how, from this common cell, the diversity of mature cell types (muscle, fat, liver, pancreas, intestine, kidney, bladder, blood, bone, thyroid, etc.) is generated, the secrets needed to regenerate and restore damaged or destroyed tissues may be unlocked.

From the cell to the organism

In each individual, the fertilized egg, a single cell, gives rise to all the cell types necessary to form a functioning human being. Each of these cell types contains an identical set of genes. Human life depends on the cooperation and specialization of all of these diverse cell types.

OBJECTIVES

To understand, treat, prevent, and cure diseases, we must understand the internal workings of each cell type in isolation; how each cell functions within a community such as tissues and organs; and how cell communication function is further integrated in the intact human body. To accomplish these goals the Working Group on From the Cell to the Organism: Unraveling the Complexity of Living Systems has delineated the following objectives.

A. CELL STRUCTURE AND ORGANIZATION

The following objectives are critical for understanding cell processes, such as how hormones generate cell response, how substances are transported in the body, and how cells metabolize fuel:

A1. OBJECTIVE: To define the mechanisms by which cells interpret and integrate signals to produce a cellular phenotype, including: the molecular-structural bases for signal transduction: the structural components of receptors, channels, pumps, transcription factors, kinase cascades, and other signal transducers that define cellular function and confer specificity; the mechanisms by which specificity of cellular responses is achieved with a common set of signaling molecules; the interplay and interaction among signal transduction pathways; the mechanisms by which signals are conveyed to the nucleus resulting in the regulation of gene expression; and the role of extracellular, cyto-and nuclear architecture in the regulation of tissue-specific gene expression.

A2. OBJECTIVE: To define novel components of relevant supramolecular assemblies and elucidate their interactions and functions.

A3. OBJECTIVE: To understand the molecular mechanisms underlying assembly, processing, localization, and turnover of macromolecules.

A4. OBJECTIVE: To elucidate the biogenesis and functions of specialized membrane compartments, such as mitochondria, vesicles, and lysosomes.

A5. OBJECTIVE: To determine how cells establish polarized domains and localize supramolecular complexes to modulate their function.

INSIGHT: A membrane surrounds each human cell. This membrane keeps the cell intact and provides an anchor for channels that open and close to allow specific molecules to enter and/or leave the cell, and for receptors, which relay messages between cells and from the environment to the interior of the cell. Many structures found within a cell are enclosed in similar membranes, all of which serve the same functions. These membranes play key roles in allowing cells to interact with each other, with their environment, and in compartmentalizing and organizing functions in a cell.

Membranes contain proteins that give each type of cell unique properties. For example specific cell types have different forms of membrane proteins that transport sugar into the cell, called glucose transporters. Uptake of the sugar glucose plays a key role in the regulation of insulin production in the pancreatic beta cell and further regulates production, storage and release of sugar by liver, muscle, kidney and fat cells. Each of these cells has an important role to play in regulating blood sugar levels and the diverse forms of the glucose transporters are key in allowing these cells to carry out their unique metabolic functions.

Membrane proteins also help transmit messages from the environment to specific cell types, regulating cell function. Cell membranes also are targets for a large number of drugs and of hormones, which bind to membrane receptor proteins. These receptors transfer the hormone signal to the interior of the cell, generating "second messengers" within the cell that regulate key cellular activities. For example, blood-forming cells have receptors for erythropoietin (Epo), a hormone made in the kidney which regulates red blood cell formation. Too little of this hormone leads to anemia and inadequate transport of oxygen within the body, causing fatigue and weakness; too much of this hormone causes excessive blood formation, increasing an individual's risk for stroke. Therapy with Epo represents one of the great successes of biotechnology, dramatically improving the wellbeing of patients with end-stage renal disease.

The 1999 Nobel Prize for Physiology or Medicine was awarded for the discovery that ''proteins have intrinsic signals that govern their transport and localization in the cell." The biotechnology industry has used these signaling mechanisms to manipulate cells to produce large quantities of insulin, growth hormone, Epo and other proteins for therapeutic use. This discovery also helps explain how errors in protein localization--arrangement of proteins within a cell or membrane--occur and cause disease. Each newly formed protein must be appropriately processed to its mature, functional form, and targeted to its correct location within the cell. Cellular proteins must be properly folded into a complex, three-dimensional structure that is essential for performing a specific function. Proteins that are not correctly folded are targeted for destruction. A number of diseases are due to folding defects in specific proteins. For example, in cystic fibrosis, deletion of one of 1284 amino acids in the CFTR protein produces a misfolded protein that is degraded rather than properly transported to the cell membrane where it normally functions as a transporter. Understanding the mechanisms by which proteins are correctly folded and transported could lead to new approaches for therapy of cystic fibrosis and other diseases.

Within each cell are specialized compartments, walled off by internal membranes, to form discrete spaces where cellular processes occur. In mitochondria energy is transferred from sugar to storage as ATP. Other compartments sort proteins, such as secreted hormones, into packages addressed for their final destinations. In the lysosomes and peroxisomes, enzymes break down food and other substances. A large number of genetic metabolic diseases arise as a consequence of defects in specific proteins required for activities that occur in these specialized compartments. For example, in storage diseases such as Hurler disease, cells and tissues are damaged by massive accumulation of material in the lysosomes that cannot be digested.

Compartmentalization occurs not only as a result of separation of activities by cell membranes, but also due to formation of supramolecular complexes. We know that an elaborate network of control mechanisms regulates and coordinates these interactions. Unraveling the mechanisms of molecular recognition leading to formation of these complexes, and the nature of the cooperative interactions which occur as a consequence, is essential to understand the mechanisms by which signaling occurs within cells. For instance, formation of such complexes is important in insulin signaling and defects in specific components of the complex may contribute to diabetes.

B. CELL DIFFERENTIATION, GROWTH AND EXPANSION

The following objectives are critical for understanding cell differentiation, proliferation and death:

B1. OBJECTIVE: To define the characteristics of pluripotent cells which permit them to progress along a specific developmental pathway or to maintain a pluripotent state.

B2. OBJECTIVE: To define the function of cell products relevant to development and differentiation.

B3. OBJECTIVE: To define the mechanisms by which commitment to a specialized cell type is initiated and maintained.

B4. OBJECTIVE: To define functional correlates of the life cycle of the cells: for example, the temporal and spatial patterns of gene expression, which explain cell proliferation, cell death and control of cell number.

INSIGHT: Every cell in the human body contains the same genes. During development, cells are programmed so that some genes are expressed and others are silent. This process is called differentiation and is responsible for the specialized characteristics that make one cell a liver cell and another a thyroid cell. The ability to control differentiation and to identify, isolate and characterize stem cells holds great potential for therapeutics, particularly tissue replacement.

Stem cells are undifferentiated cells that can give rise to many cell types. Totipotential stem cells can give rise to an entire organism. Pluripotent stem cells can generate all the cell types of an organism, but not the entire organism. Other types of stem cell can give rise to a more limited repertoire of differentiated cells. For example hematologic stem cells can generate all types of blood and many bone cells. An array of stem cells can now be isolated from mice and other research animal models and tools are being developed to identify, characterize and purify these cells. These cells hold promise for development of therapeutics and replacement tissues through understanding of control of their differentiation.

Recently, two groups of scientists have succeeded in isolating and culturing the first human pluripotent stem cell lines. These cells can give rise to all of the different types of specialized cells in the body, yet they are not totipotent and thus cannot give rise to an entire human being. The excitement surrounding this discovery lies in the ability of these cells to divide and self renew as well as to commit to become cells with more specialized function, such as liver, blood, bone or pancreatic beta cells. The use of these cells for transplantation to replace or repair damaged tissue is discussed under therapeutic applications, later in this chapter. To make these applications a reality, fundamental research is needed to identify the signals that direct the differentiation of a stem cell and cause it to develop into a specific cell type. Understanding the cellular decision making process will give us the tools to direct pluripotent stem cells to become the cells and tissues needed for transplantation.

It is by the growth and division of cells that organisms are formed. Cell growth and division is organized into a cycle of events. This cell cycle is influenced by external regulatory signals. Although formation of new cells and cell death might appear to be opposing processes, they are closely coupled. Apoptosis, or programmed cell death, is a normal consequence of cell proliferation. This cell suicide mechanism enables control of cell number and eliminates individual cells that threaten the body's survival. Certain cells have unique sensors, termed death receptors, on their surface which recognize signals from outside the cell and trigger cell death. Survival signals from nearby cells may block this death mechanism. This communication regulating apoptosis is critical to immune system function. One type of cell targeted for destruction is that which recognizes self. A malfunction in elimination of these cells can lead to an attack on the body's own cells, resulting in autoimmune disease, such as type 1 diabetes or inflammatory bowel disease.

Cell proliferation and death are closely regulated processes. Mechanisms to replace worn out cells or make more cells are highly regulated. While some cells are very short-lived and are continually replaced, others cannot reproduce and cell death leads to a permanent deficit. Even small imbalances in cell number can have devastating consequences. For example, the cells that form and remodel bone are continuously dying and being replaced by new cells arising from the bone marrow. Changes in the numbers of these active bone cells due to altered rates of cell proliferation or cell death can lead to bone loss. The gastrointestinal tract provides another example of the catastrophic consequences of altered regulation of cell growth. When the gene for a transcription factor (which regulates expression of other genes) was "knocked out" in mice, the animals died shortly after birth because their intestinal lining cells could not regenerate and properly absorb food. In contrast, mutations in a gene involved in the regulation of this same transcription factor causes excessive cell growth and tumor formation in the colon.

C. ORGANIZATION OF CELLS INTO TISSUES AND ORGANS

The following objectives are important for understanding organization of cells into tissues and organs:

C1. OBJECTIVE: To define fundamental mechanisms of organogenesis, including cell migration, differentiation, and cell-matrix and cell-cell interaction.

C2. OBJECTIVE: To define the mechanisms that promote and restrict cell growth and proliferation, so that each organ and tissue maintains only the proper number and size of cells of each type in the proper spatial distributions during ontogeny, repair and regeneration.

C3. OBJECTIVE: To determine how cell-cell interactions influence organ function.

INSIGHT: Much remains to be learned about how cells organize to form tissues and how tissues then form organs. We know that connections between cells must be precisely ordered. During development, tissues are formed from cells originating in various parts of the body. How do migrating cells reach their destination and how do organs form in particular locations? This process requires that cells selectively recognize each other and attach. To accomplish this, cells produce an extracellular matrix, a network of secreted proteins and carbohydrates, which helps to bind cells together and forms a lattice through which cells can move. This matrix also serves as a reservoir for hormones that control cell growth and differentiation and mediates interactions important for wound healing and tissue repair and regeneration.

Of particular importance for NIDDK is understanding how cells unite to form epithelial tissues, the sheets of tightly bound cells that line all the cavities and free surfaces of the body, including the gastrointestinal tract, bile and pancreatic ducts, kidney collecting ducts, ureter, bladder and skin. Epithelial tissues have specialized junctions between cells, forming seals to separate fluids with different compositions on each side of this barrier. Each type of epithelia is specialized to accomplish particular functions. The epithelial cell layer separating the intestinal lumen from the blood is specialized to permit the absorption of nutrients and their transfer from intestine to blood. Renal tubular epithelium, the site of damage in acute renal failure, has important reabsorptive, metabolic and endocrine functions. Knowledge of its role in maintaining homeostasis is essential to development of strategies to replace these lost functions and reduce the high mortality associated with this condition.

The origins of a number of diseases lie in the failure to correctly generate components of the highly ordered cell architecture of tissues and organs. We know that proper formation of specific cell types in the pituitary requires a precise balance among the factors that regulate gene expression in these cells. From this knowledge has emerged an understanding of how some forms of dwarfism, as well as more generalized disorders involving growth and reproductive and thyroid function, arise from genetic changes which impair the formation of specific pituitary cells. To uncover the mechanisms of cyst formation and growth in polycystic kidney disease, the role of the polycystins, the products of the disease causing genes, in development and function of the normal kidney must be understood.

D. INTEGRATED CELL FUNCTION AND ENVIRONMENTAL RESPONSE

The following objectives relate to understanding the interaction of cells and tissues with each other and with their environments:

D1. OBJECTIVE: To understand how signaling processes are integrated among individual cells and interact to create networks with coherent and predictable functions.

D2. OBJECTIVE: To understand the integrated combinatorial nature of local environmental signals.

D3. OBJECTIVE: To understand how specialized cells and tissues modulate other cells in their local environment.

D4. OBJECTIVE: To define the mechanisms by which specialized cells and tissues interact with immunocytes and immune mediator molecules.

D5. OBJECTIVE: To understand the interaction of the cell with its metabolic environment.

D6. OBJECTIVE: To understand mechanisms by which cells adapt to unusual environments, such as extremes of pH, oxygen tension, or osmolarity.

D7. OBJECTIVE: To define the interplay of cells, tissues and organs to regulate homeostasis of the intact organism, such as regulation of glucose, salt and mineral concentrations.

INSIGHT: Intercellular signaling is necessary for cooperation between specialized cell types and for the capacity of specialized tissues to function in an integrated fashion. This is particularly apparent in the hypothalamus, a brain region with a critical role in integrating neural control of the endocrine system and endocrine control of neural function. Here communication occurs almost exclusively through chemical messengers; cells influence adjacent cells with their secretions and signaling pathways connect neighboring regions whose integrated function is essential for regulation of appetite and thirst, response to stress, reproductive function, metabolism, and salt and fluid balance. Understanding the complex interconnections between specialized hypothalamic cells, which make and respond to key hormones and neurotransmitters involved in appetite regulation, will provide targets for pharmacologic approaches to control food intake and weight gain. The hypothalamus also has a key role in sensing and responding to hypoglycemia. Understanding the signaling pathways involved is important for prevention and reversal of hypoglycemia unawareness, a key problem limiting therapy of people with diabetes.

Understanding the cell signaling pathways involved in maintenance of tolerance and pathways that trigger immune activation are prerequisites for the development of new therapies to prevent or reverse autoimmune diseases and to prevent rejection of transplanted organs and cells. The molecular signals that govern immune cell communication are the targets for new approaches to immune modulation. Immune cells called T cells have one receptor responsible for accurately identifying a potential target. More recently, these cells were found to have a second signaling system involving a costimulatory receptor which activates the T cell once target recognition has occurred. Now a number of agents have been developed that interfere with this costimulatory receptor. By blocking the specific immune cells that attack transplanted tissue, these drugs may be safer and more effective than immunosuppressive drugs in preventing transplant rejection. This approach to redirecting the immune system to maintain tolerance may also be useful in restoring self-tolerance in autoimmune diseases.

Wound healing is a process that involves extensive interaction of cells and tissues with their local environments. In the area of a skin ulcer, a network of secreted proteins and carbohydrates, called the extracellular matrix, fosters interaction of the local affected cells with blood cells and growth factors secreted locally. Blood cells infiltrate the wound and attach to the extracellular matrix where they are transformed into specialized cells to cleanse the wound, and initiate and propagate new tissue formation. The extracellular matrix helps with the formation of new blood vessels needed to sustain the new tissue. Local release of growth factors stimulates these processes. In diabetes, high blood sugar, reduced delivery of oxygen and other nutrients due to vascular disease, and other alterations in the local metabolic environment can impede this healing process.

Our cells function best in a carefully controlled environment maintained by a complex system of regulatory networks designed to maintain key parameters within the narrow range optimal for health. Hormones are essential to regulate cell function to maintain this internal environment. For example, calcium concentration is tightly controlled by hormonal mechanisms. Specialized cells in the parathyroid gland have a calcium sensor that triggers rapid release of parathyroid hormone (PTH) in response to any fall in blood calcium levels. PTH stimulates release of calcium from bone, reabsorption of calcium from urine, and activation of vitamin D to enhance absorption of calcium from the intestine. The ensuing rise in calcium then stimulates mechanisms to shut off a further rise in calcium and inhibit further PTH release. Similar regulatory mechanisms, involving synergistic effects of multiple hormones on many organs and tissues, exist to maintain blood sugar and salt concentrations, fluid balance, blood pressure and other critical parameters within narrow limits. These involve coordination of simultaneous responses involving multiple hormones, counterbalancing influences to fine tune responses, and mechanisms to terminate the hormone response.

Many drugs affect multiple tissues, with effects on one tissue conferring benefit, while risks or side effects derive from effects on another tissue. For example, estrogen replacement therapy is clearly beneficial in preserving bone mass, yet its effects on the cardiovascular system, blood clot formation, breast and other tissues are less well understood. The recent discovery of two separate estrogen receptors with different tissue distributions and new understanding of how the estrogen receptor interacts with other signaling molecules within cells to turn genes on and off have important implications for development of more selective drugs. These "designer estrogens" are intended to produce beneficial effects of estrogen in some tissues and to actually antagonize harmful effects in other tissues. Diverse effects on different tissues are also seen with thiazolidenediones, a class of drugs, which activate the nuclear receptors that modulate gene expression in response to fatty acids and lipid metabolites and are currently being used as insulin sensitizers in the treatment of type 2 diabetes. These drugs, originally shown to cause differentiation of fat cells, were more recently implicated in the formation of scavenger cells that take up lipids and in the inhibition of apoptosis in colon cells; recognition of these latter effects stimulated investigation of their possible effects on atherogenesis and intestinal tumors. The drug discovery process could be streamlined if cultured cell lines or other methods were available to determine or predict the integrated effects of a drug on the many cells and tissues of the intact organism.

E. THERAPEUTIC APPLICATIONS

The following objectives are important to developing therapeutic applications based on understanding of cell biology:

E1. OBJECTIVE: To define key molecules and critical pathways which are essential for specialized cell function and which must be provided and/or regulated to enable functional replacements for specialized cells.

E2. OBJECTIVE: To identify key targets for molecular modulation to promote cell regeneration and repair.

E3. OBJECTIVE: To understand factors that maintain stem cells and control their commitment, as a precursor to their use for tissue/organ replacement.

E4. OBJECTIVE: To devise methods to enhance growth and yield of cells produced and modified for therapeutic purposes.

INSIGHT: The life-saving value of donated kidney, liver, intestine, pancreas and other organs is well established, yet the number of people who could benefit from transplantation far outstrips the number of organs available for transplantation. Pluripotent stem cells have the potential to serve as a renewable source of replacement cells and tissues to treat many diseases important to NIDDK. The Institute is committed to applying insights derived from basic investigations of cell biology to realize the promise of stem cell therapy as well as develop better methods of cell and organ transplantation and methods to stimulate tissue regeneration.

Stem cell biology may have important applications, not only for transplantation, but also for differentiation therapy using an individual's own cells. During fetal development, pluripotent stem cells develop into types of stem cells with more limited capacities to form specialized cells. For example, hematopoietic stem cells can form all the blood cells and some bone cells, but not other tissue types. Our bodies contain many types of stem cells that could be used to repair or regenerate some tissues. Research is needed to identify cells with these capacities and to develop methods to stimulate their differentiation into specialized cells. We know that the human body has the ability to permit new growth and renewal of liver, intestinal lining, renal tubule, bone, skin and other cells. We must discover whether this ability also exists for other critical cell types, such as pancreatic beta cells, and discover methods to enhance the body's regenerative capacity.

Cellular engineering is another promising approach to replace vital functions lost to tissue destruction. Development of such therapies requires an understanding of the molecular mechanisms underlying the unique functions of each cell type so that these can be recreated in the therapeutic cells. For example, if we can define every step in the process by which the beta cell senses the level of blood glucose and modulates the secretion of insulin in response to changing blood glucose, we could attempt to recreate this process in a therapeutic cell protected from autoimmune destruction. In these therapeutic cells, genes and regulatory elements would be introduced to provide the functional components needed to mimic the specialized cell function to be replaced. Cell engineering may also be a useful approach to induce tolerance once we know which genes should be introduced to accomplish this. Yet another application of cell engineering involves creation of animal models, which mimic human disease processes, and can be used to test promising therapeutic approaches.

IMPLEMENTATION STRATEGIES

The Working Group From the Cell to the Organism: Unraveling the Complexity of Living Systems developed the following strategies accomplish the objectives identified above:

A. CELL STRUCTURE AND ORGANIZATION

A1. STRATEGY: Apply microarray technology and computational biology to the study of the regulation of gene expression: specifically, to understand the relationship between strength and duration of a stimulus and the response of a gene.

A2. STRATEGY: Develop methods to measure very low concentrations and affinities of molecules in cells.

A3. STRATEGY: Encourage new efforts to use biochemical approaches to study protein-protein interactions.

A4. STRATEGY: Encourage the use of mass spectroscopy to identify protein components in macromolecular complexes.

A5. STRATEGY: Encourage new efforts at determining the three dimensional structure of proteins and macromolecular assemblies, using methods such as NMR, immuno-electron microscopy and 3D imaging.

A6. STRATEGY: Enhance understanding of dynamic interactions of macromolecules in living cells, employing methods such as fluorescence energy transfer.

A7. STRATEGY: Develop new optical methods to study sub-nuclear organization in the context of living cells.

A8. STRATEGY: Develop in vivo imaging methods to monitor the organization of molecules in supramolecular complexes and subcellular organelles and encourage the establishment of functional assays that reconstitute interactions between such assemblies and organelles.

B. CELL DIFFERENTIATION, GROWTH AND EXPANSION

B1. STRATEGY: Apply information from model organisms to understanding cell differentiation, proliferation and death in higher vertebrates.

B2. STRATEGY: Develop systematic approaches to study gene expression patterns during different stages of development and the cell cycle.

B3. STRATEGY: Use the power of computational biology (i.e. pathway prediction analysis) and comparative genomics to understand functional integration in cells and tissues.

B4. STRATEGY: Develop techniques for rapid and efficient analysis of changes in protein expression in whole cells and whole tissues.

B5. STRATEGY: Identify promoters with desirable properties such as lineage and cell specificity.

B6. STRATEGY: Identify cell lines in which differentiation can be directed and develop tissue culture methods to study cell differentiation.

C. ORGANIZATION OF CELLS INTO TISSUES AND ORGANS

C1. STRATEGY: Develop in vivo measurements to quantitate and assess the effect of gene perturbations.

C2. STRATEGY: Utilize model organisms to gain insight into the roles of single genes that operate in complex systems.

C3. STRATEGY: Develop simple and efficient methods to modulate gene expression in intact animals or organ culture.

C4. STRATEGY: Produce antibodies to epitopes within specialized regions of extracellular matrix to define the composition of the matrix and understand its function.

C5. STRATEGY: Develop optimized, chemically-defined media and matrices for propagation of cells, tissues and organs.

D. INTEGRATED CELL FUNCTION AND ENVIRONMENTAL RESPONSE

D1. STRATEGY: Understand the molecular mechanisms by which cells act as sensors.

D2. STRATEGY: Learn how to measure the concentrations of paracrine factors near or on cells and develop methods to detect single or small numbers of extracellular molecules in vivo.

D3. STRATEGY: Develop model hormonal environments that incorporate pulsatility.

D4. STRATEGY: Develop methods to look at the response of an entire organism to agents that may engender disparate responses in different tissues.

D5. STRATEGY: Use non-invasive imaging to understand physiologic functions at an organism level.

D6. STRATEGY: Apply information from model organisms to understanding function in higher organisms.

D7. STRATEGY: Use the power of computational biology and comparative genomics to understand the integration and interplay among cells, tissues, organs and environmental factors, nutrition and toxins on the organism.

E. INJURY AND REPAIR OF CELLS, TISSUES AND ORGANS

E1. STRATEGY: Analyze the role of the immune system in causing disease and injury, both in diseases known to be caused by specific infectious agents, as well as diseases in which the primary cause is unknown.

E2. STRATEGY: Analyze the basis of tolerance using animal model systems with state-of-the-art techniques, including transgenic animals and DNA arrays, that allow for dissection of each component of immune cells, cytokines, and growth factors.

E3. STRATEGY: Examine the role of hemodynamic factors and ischemia in injury to cells, tissues and organs, dissecting the steps of ischemic injury and the process through which hypoxia leads to cell death.

E4. STRATEGY: Evaluate the mechanisms of repair of epithelial cell injury.

E5. STRATEGY: Evaluate the mechanisms of regeneration in response to injury of liver, pancreas, kidney and hormonal organs.

E6. STRATEGY: Evaluate the mechanisms of fibrosis that can result from different forms of injury, but have an impact on a range of diseases and conditions.

E7. STRATEGY: Elucidate the impact of behavior on diseases through the study of preclinical models.

E8. STRATEGY: Study the influence of nutritional factors such as anti-oxidants in ameliorating damage to cells, tissues, organs in animal models of disease.

F. THERAPEUTIC APPLICATIONS

F1. STRATEGY: Encourage basic stem cell research.

F2. STRATEGY: Develop novel methods to safely culture and expand cells without transformation.

F3. STRATEGY: Develop new ways to increase the quantity and viability of tissues harvested from cadavers and living donors for transplantation.

F4. STRATEGY: Develop a deeper understanding of immune tolerance and rejection.

F5. STRATEGY: Explore innovative, less toxic ways of preventing rejection, such as inducing immune tolerance or cell encapsulation.

F6. STRATEGY: Devise methods and innovative delivery systems to promote controlled cell and tissue regeneration in patients.

F7. STRATEGY: Identify novel cell components that can serve as new targets for drug discovery.

F8. STRATEGY: Develop cell systems and animal models of different types of injury that are appropriate for assessing therapies.

F9. STRATEGY: Develop therapeutic strategies that enhance or modify immune response to mediate clearance of persistent pathogens and terminate chronic infections or ameliorate and limit autoimmune disease.

F10. STRATEGY: Develop improved gene therapy methodologies applicable to humans.

F11. STRATEGY: Develop transplantation models and apply these to assess methods of inducing tolerance.

PREVENTION AND TREATMENT OF DISEASE: EPIDEMIOLOGY AND CLINICAL INVESTIGATION

Overall Goals: (1) To move advances in science and technology into patient-oriented applications in a timely and efficient manner; and (2) to develop targeted interventions for diseases and complications that are tailored to the needs of specific individuals and populations.

BACKGROUND

Opportunities and Challenges

As stated earlier in this document, the NIDDK has responsibility for areas of clinical research related to many diseases, including cystic fibrosis, diabetes, digestive diseases, endocrine disease, hematologic diseases, inborn errors of metabolism, kidney diseases, liver diseases, nutrition, and urologic disease.

These diseases affect individuals of all ages, are often chronic with a long natural history, and may cause significant morbidity and reduced life expectancy. In addition, they usually require long-term management, burdensome self-management, and long-term coping by affected individuals and their families.

Many diseases within the NIDDK's research mission also may have several elements that affect the natural history of the disease. For example, there may be genetic, environmental, and behavioral factors that influence the development of the disease, disease progression, and final outcomes. There is also considerable variability in an individual's susceptibility to the effects of the disease, as well as certain populations that may have increased or decreased risk, including children, racial and ethnic minorities, women, men, and the elderly.

Advances in basic and clinical science are leading to a greater understanding of the causes and mechanisms of these diseases and their complications. Many new interventions, for example, are available that have the potential to prevent, cure, or ameliorate the complications of diseases within the research mission of the NIDDK. Furthermore, application of new or improved technologies will make it possible to identify risk factors for disease occurrence and progression, which will stimulate new research directions.

Expanding the knowledge base of disease through clinical research, based on advances in basic science and technology, is critical to develop effective strategies for disease prevention. With greater knowledge and understanding of the disease processes and their effects on different individuals and populations, it will be possible to develop interventions that are specifically targeted to their needs.

OBJECTIVES

The NIDDK conducts clinical research on all aspects of disease prevention: primary prevention for those who are at risk for developing disease; secondary prevention for those who have the disease; and tertiary prevention for those who have developed complications of the disease. This comprehensive approach is needed to ensure the best possible outcomes for people who are at different stages in the disease process.

However, through the Strategic Planning process, NIDDK, working in collaboration with its National Advisory Council, the scientific community, and lay and professional organizations, identified several barriers that impede the development and implementation of new prevention and treatment strategies for the diseases within the research mission of the NIDDK. These barriers include research infrastructure; scientific understanding; and the identification and recruitment of volunteers to participate in the evaluation of new prevention strategies.

The following objectives are meant to address these barriers in such a way as to achieve the overall goals of (1) moving advances in science and technology into patient-oriented applications in a timely and efficient manner, and (2) developing targeted interventions for diseases and complications that are tailored to the needs of specific individuals and populations.

OBJECTIVE: Increase and enhance the research infrastructure by addressing the issues of manpower shortages and insufficient information resources.

INSIGHT: At present, there is limited capacity within the research community to develop and evaluate the many new treatments and prevention strategies that are currently available. This limitation will increase as more new approaches to disease treatment and prevention are developed. For example, there is a manpower shortage because biomedical research scientists are not choosing careers in clinical research. Those who do choose careers in clinical research find that there is insufficient infrastructure to support their research. In addition, there are insufficient resources in the areas of biostatistics, bioinformatics, data management, laboratory support for clinical studies, and for recruitment and retention of research volunteers. As a result of these limited resources, there are often long delays in planning, organizing, and implementing clinical trials, and only a few large trials can be conducted concurrently.

OBJECTIVE: Advance the science knowledge base so as to gain a better understanding of the natural history of disease based on more precise characterization.

INSIGHT: Many of the diseases within the NIDDK research mission are affected by complex interactions between behavior, genetics, and the environment. These factors, coupled with variability in individual susceptibility to the disease processes, make the design and conduct of clinical studies difficult, and impede the development of targeted interventions for specific populations and individuals. Thus, there is a need for much better phenotyping and genotyping of the diseases within the mission of NIDDK, and for better understanding the natural history of the diseases based on more precise characterization.

OBJECTIVE: Identify, recruit, and retain more research volunteers.

INSIGHT: Evaluation of new prevention and treatment strategies developed in animal studies must eventually be evaluated in humans. Because of the unique and complex nature of humans, many prevention strategies can only be tested in humans. In particular, identification of potential research volunteers is a major obstacle for the uncommon or rare diseases within the NIDDK's research mission. A nationwide or even worldwide recruitment effort is often needed, because no one particular center has sufficient numbers of patients to participate in clinical research.

Once potential research volunteers have been identified, there are significant barriers to their participation in clinical studies and clinical trials. For example, currently available research methods are often time-consuming and entail inconvenience and discomfort that many subjects find unacceptable. The study of self-selected patients who are willing to undergo the necessary inconvenience and discomfort limits the generalizability of research findings. In addition, there are often historical, cultural, and language barriers that discourage the participation in clinical research, often of the individuals who would derive the greatest benefit from the research advances.

Finally, advances in science and technology are encountering significant ethical, legal, and social barriers to the participation of individuals in clinical research. These barriers relate to the participation of children in clinical research, the identification of disease susceptibility, informed consent, insurability, job discrimination and job security.

IMPLEMENTATION STRATEGIES

To achieve the objectives stated above, the Working Group on Prevention and Treatment of Disease; Epidemiology and Clinical Investigation, developed the following strategies:

A. STRATEGY FOR DEVELOPING CLINICAL RESEARCH INFRASTRUCTURE

The NIDDK believes that the most efficient strategy to build a stronger clinical research infrastructure is to establish dedicated clinical research and clinical trial networks in selected areas of interest. Specific areas will be targeted for development based on scientific opportunity, disease burden on individuals and society, and on the need for a multicenter approach to the disease.

The charge to a particular network also will depend on the knowledge base and scientific opportunity. Thus, networks might be charged with conducting clinical research in areas of interest, epidemiologic studies, or clinical trials using state-of-the-art techniques. For some diseases, pilot and feasibility studies of new interventions are needed to evaluate and prioritize them for future large-scale trials. These networks might also conduct clinical trials in rare and orphan diseases, or where there are major public health questions that require a large, multicenter study. Collaboration with industry, rather than competition with industry-sponsored clinical trials, will be the most efficient utilization of manpower and other resources.

The components of the individual networks will depend on the specific disease or diseases under study. NIDDK envisions supporting key research personnel, biostatistics and research coordinating functions, central laboratories where necessary, and bioinformatics to facilitate recruitment of individuals into clinical studies and trials. Efficient functioning of the networks will require mechanisms to assess potential studies and interventions and prioritize the research agenda. Funding for pilot and feasibility studies will be provided in specific instances to facilitate timely evaluation of new interventions.

B. STRATEGY FOR DEVELOPING BETTER METHODS FOR STUDYING NORMAL AND DISEASE PROCESSES IN HUMANS

NIDDK will support research to develop new or improved methods for studying normal and disease processes in humans. The development of non-invasive or minimally invasive methods is viewed as essential to increase the science knowledge base, and to encourage participation of research volunteers. Better processes are needed to assess organ size and function, pathologic processes, and physiology. Better methods are also needed for screening, diagnosis, and staging of many diseases within the mission of NIDDK. New or improved methods for studying human behavior and its role in disease processes are also needed. Methods are also needed to predict progression of disease. Surrogate measures of disease outcomes are needed to shorten the duration of clinical trials and to allow evaluation of a greater number of interventions concurrently.

C. STRATEGY FOR DEFINING DISEASES MORE PRECISELY

With the development of clinical research infrastructure and new or improved methods for studying normal human functions and disease, it will be possible to precisely define the diseases within the research mission of the NIDDK.

Precise phenotypic definition of disease is a critical first step in discovering the genetic factors that underlie the disease. Subsequently, the NIDDK will support research to phenotype diseases of interest, including biochemical, physiologic, histologic, anatomic, behavioral, and sociodemographic measures. Close collaboration between clinical researchers and geneticists will be encouraged and supported. Once the genetic factors are discovered, newly emerging array technology will make it possible to precisely genotype individuals within the population. Genotyping, along with precise phenotyping, will lead to the design of better clinical studies and clinical trials of targeted interventions that are tailored for specific disease processes.

D. STRATEGY FOR APPLYING STATE-OF-THE-ART METHODS

With the development of the clinical research infrastructure, new or improved methods for studying normal function and disease, and more precise phenotyping and genotyping, it will be possible to increase understanding of the diseases within the NIDDK's research mission.

The NIDDK will support research to identify the factors accounting for health disparities among different populations and the development of targeted interventions tailored to the needs of specific populations. The NIDDK also will support research that defines the role of environmental factors in disease, including drugs, toxins, viruses and other infectious agents, behavior, stress, and nutrition. With an increase in the knowledge base it will then be possible to develop targeted intervention for minority populations, children, men, women, and the elderly.

E. STRATEGY FOR ADDRESSING THE ETHICAL, LEGAL, AND SOCIAL BARRIERS TO CLINICAL RESEARCH

The ability to precisely phenotype and genotype individuals at risk for, and with disease requires careful consideration of the potential risks to the individual. These include the risks of the research itself, particularly in children, and the threats to insurability and job security that discovery of disease susceptibility may entail. Psychosocial effects resulting from the discovery of disease susceptibility may be significant. Research is needed to understand these effects, and to develop management strategies.

The NIDDK will support research in these areas, and will work with the scientific and lay communities to address these ethical, legal, and social barriers to clinical research on disease prevention and treatment.

F. STRATEGY FOR DEVELOPING AND INVESTIGATING NEW APPROACHES TO DISEASE PREVENTION AND TREATMENT

Advances in basic and clinical research and technology will make it possible to develop new approaches to disease prevention and treatment.

The NIDDK will support research on new therapeutic approaches, including new approaches to changing lifestyle and behavior, and new or improved treatments such as pharmacotherapy, cellular therapy, transplantation, immune modulation, and gene therapy.

The NIDDK also will encourage and support research on the application of engineering and bioengineering technologies to disease prevention and treatment. Translational research will ultimately be required for successful implementation of new therapeutic approaches into practice, and will also be encouraged and supported.

Finally, as better treatments and interventions are discovered, it will be important to understand their effects on cognitive function, family function, psychiatric disorders, and quality-of-life.

RESEARCH INFRASTRUCTURE

Overall Goals: (1) To attract the best scientific talent within the research mission of the National Institute of Diabetes and Digestive and Kidney Diseases; and (2) to retain talented researchers over the full course of their investigative careers (3) and to improve the condition and availability of the research resources and research tools needed to enhance the conduct research within the scope of the NIDDK mission.

BACKGROUND

Successful research programs depend upon ideas, technology, appropriately trained individuals to perform the research and the infrastructure to conduct the research. The availability and condition of biomedical research space, in turn, affects the scope and quality of the research conducted by the research organizations supported by the NIDDK. Common themes identified by all the Working Groups relating to this section of the Plan include the need for improved research infrastructure and capacity, including the need to attract and retain talented investigative researchers, recruit more volunteers to participate in the evaluation of new disease-prevention treatments, increase the number of model systems for our studies, and make data more accessible to a wider audience through the use of new bioinformatics technologies.

OBJECTIVES

TRAINING AND CAREER DEVELOPMENT

Currently, the NIDDK supports a full spectrum of research training and research career development awards. More than 700 individuals pursue pre- and post-doctoral training under the National Research Service Act, and approximately 250 individuals pursue more advanced, mentored research experiences supported by various research career development awards. This support program is continuously monitored by the NIDDK program staff and by the NIDDK Advisory Council to ensure that awards are properly focused on the needs of the scientific community and that their terms encourage the most talented minds to train in the areas supported by NIDDK.

The half-life of an investigator receiving support from NIH as a Principal Investigator, however, is approximately 6 years. This is an incredibly short time considering the many long, expensive years that are necessary to prepare an investigator for independent research.

For the NIDDK to achieve its research objectives will greatly depend on its ability to develop a cadre of bright, well-trained, and highly motivated investigators. To ensure that such a cadre of scientists are ready and able to exploit the opportunities detailed in the NIDDK's five-year Strategic Plan, the Institute must commit a substantial portion of its available resources to attracting the best scientific talent to health problems within the research mission of the Institute. It must also work to retain talented individuals in research over the full course of their investigative careers.

To these ends, the Working Group on Research Infrastructure developed the following objectives. These objectives are cross-cutting and apply to all research program areas of the NIDDK:

A1. OBJECTIVE: Encourage physician-scientists to select careers in biomedical research, and provide them with opportunities for lifelong careers.

INSIGHT: In December 1997, the NIH Director's Panel on Clinical Research characterized the present state of clinical research as follows:

"At first glance, it seems impossible to believe that a crisis in clinical research is at hand because a career in clinical research today would appear more rewarding than ever. Advances in molecular medicine are providing enormous scientific opportunities. Never before has the bench-to-bedside interface been more exciting and productive. Never before have clinical trials been more promising as new products of the genetic revolution flow from pharmaceutical and biotechnical companies. The era of managed care, while challenging in the extreme, has also opened opportunities for outcomes analyses and epidemiology that would never have occurred in the absence of a demand for a more quantitative approach to the results of medical care. Yet this Panel has gathered data that show that the ratio of M.D. to Ph.D. applicants for NIH support has progressively fallen over the past thirty years even though success rates for the two types of applicants are similar. Importantly, the absolute number of M.D. applicants has fallen further in the past three years. Furthermore, M.D.s who fail to achieve fundable priority scores from study sections following their initial applications are less likely to reapply than Ph.D.s. This represents a dispirited attitude among M..D. faculty members that bodes ill for the future of academic medicine and the public's health. The sense of excitement, opportunity and determination that should permeate the field is compromised by financial and career anxieties."

The Panel made the following recommendations for improving the training of clinical investigators:

• The NIH should initiate training programs that will enhance the attractiveness of careers in clinical research to medical students.

• The NIH should improve the quality of training for clinical researchers by requiring grantee organizations to provide formal training experiences in clinical research and careful mentoring by experienced clinical investigators.

• The NIH should initiate substantial new support mechanisms for young and mid-term clinical investigators, if possible in collaboration with the private sector.

• A loan repayment program for clinical investigators should be instituted.

Since the publication of the NIH Director's Panel on Clinical Research report, the NIH and the NIDDK have responded to several of these recommendations.

• The NIH initiated three new targeted awards. The K23 award supports training of new investigators in patient oriented research, the K24 award offers similar support for mid-career clinical investigators, and the K30 award offers support to institutions for the development and implementation of curricula related to patient oriented research. The NIDDK supports all three of these awards.

• In FY 1999, the NIH significantly raised the stipends offered under National Research Service Act (NRSA) awards.

• Similarly, the NIDDK has upgraded the attractiveness of its mainstay career development award, the K08, by raising the maximum salary compensation to a maximum of $75,000. The NIDDK also offers K08 holders the opportunity to compete for small grants, to be held along with their K08s, to allow them to initiate a research program of significant proportions during the last two years of their career awards.

While these awards and improvements are too new to be evaluated at this time, they have drawn impressive numbers of well-qualified applicants, and the NIDDK has significantly increased the numbers of career development awards it supports.

A2. OBJECTIVE: Increase the numbers of well-trained investigators and support staff capable of conducting research to eliminate the health disparities in all segments of the population.

INSIGHT: Minority groups in the U.S. suffer disproportionately from many of the diseases that are within the NIDDK's research mission. For example, the prevalence of type 2 diabetes in African Americans is approximately 70 percent higher than in whites, and the prevalence in Hispanics is nearly double that of whites. The Pima Indians of Arizona have the highest known prevalence of diabetes in the world.

Despite these statistics, minority groups have not been adequately represented in many research studies, and culturally sensitive approaches are needed to design appropriate clinical studies of the health problems of these populations and to encourage minority group participation in them.

The NIDDK has developed a multi-faceted program targeting the reduction or elimination of disparities in health status among population groups, and it is developing interventions focused on the prevention and treatment of specific diseases in particular subpopulations. For example, the Institute is currently carrying out the Diabetes Prevention Program, a randomized clinical trial to evaluate the preventative effect of programs for weight loss and exercise on the onset of type 2 diabetes mellitus in high risk populations. Of the subjects enrolled in this study, approximately 50 percent are members of minority groups disproportionately affected by this disease.

Unfortunately, despite the many programs funded by the NIDDK to reduce or eliminate health disparities and to increase the numbers of investigators with special interests in this area (many of them members of the minority groups themselves), the number of such investigators remains very small and may be decreasing as a proportion of the overall biomedical research workforce. This must be remedied immediately, and the NIDDK must find ways to increase the numbers of well-trained investigators dedicated to addressing and eliminating health disparities among groups in the U.S. population.

A3. OBJECTIVE: Increase the numbers of investigators who are members of groups that are underrepresented in biomedical science.

INSIGHT: The NIH recognizes the need to increase the number of underrepresented minority scientists participating in biomedical and behavioral research as a means of addressing a potential research labor shortage in the twenty-first century. As of 1992, underrepresented minorities constituted only 4.5 percent of the postdoctoral fellows in the life sciences and less than 2.7 percent of the principal investigators of NIH research grants. Currently, the American Association of Medical Colleges estimates that only 2.8 percent of the medical school faculty members in the U.S. are African American and 3.1 percent are Hispanic.

While the NIDDK has a multi-faceted program of support to encourage underrepresented minority group members to enter the scientific workforce in its areas of responsibility, more must be done in this regard.

A4. OBJECTIVE: Develop programs to encourage the interest of investigators from outside traditional biology in problems related to the NIDDK's areas of responsibility, including materials scientists, physicists, mathematicians, bioengineers.

INSIGHT: Many of today's biological problems are too complex to be solved by biologists alone. Therefore, research partnerships across many disciplines are needed, including physics, mathematics, chemistry, computer science, engineering, and bioinformatics. The creativity of interdisciplinary teams is resulting new basic biologic understanding, novel products and new technologies. The NIDDK is undertaking a number of initiatives intended to foster such partnerships. For example, the NIDDK has an initiative to stimulate research on the development of techniques or reagents leading to the ability to image pancreatic beta cells in vivo. Information gained from such projects will contribute to the development of a clinical exam that can be used for monitoring disease progress in diabetes, as well as patient response to certain therapies. Another initiative is intended to stimulate research on the development of imaging methods to assess cyst growth and provide markers of disease progression for polycystic kidney disease. In both initiatives, because of the highly specialized nature of the work, imaging experts are encouraged to collaborate with cell biologists, chemists, engineers, and clinicians.

A5. OBJECTIVE: Ensure that entry into the competition for research funding is facilitated for new investigators.

INSIGHT: Although it is important to offer support to trainees at all stages of their development, a crucial test of the entire process is whether they can make the transition from mentored to independent investigator status.

A6. OBJECTIVE: Develop mechanisms for providing focused training programs for new and experienced investigators in new methods and technologies.

INSIGHT: The tremendous acceleration in pace of scientific discovery over the last decade, coupled with development of many new high-throughput technologies, has created an era of unparalleled opportunity to uncover the causes of disease and identify effective therapies. For example, the recent development of genome-wide expression profiling (chip, microarray or Serial Analysis of Gene Expression [SAGE] technologies) enables a comprehensive high-throughput screening of the effects of an insult (genetic, physiologic, pathologic, etc.) on gene expression in tissues and specific cell populations of interest.

These techniques may aid in determining the function of a newly discovered gene or discovering new biomarkers and therapeutics for patients with disease. Many investigators with on-going research programs want to integrate this and other emerging technologies into their research. However, acquiring the skills to bring a given technology into a laboratory can be a significant barrier to its productive use.

IMPLEMENTATION STRATEGIES

The Working Group on Research Infrastructure identified several barriers to achieving the objectives stated above. Top among those barriers is inadequate funding. For patient-oriented research, in particular, the funds available for clinical research are inadequate to support the number of investigators needed. Also, there are too few clinical studies and trials in the NIDDK's areas of interest to provide continuous funding opportunities for investigators.

The Working Group on Research Infrastructure, therefore, believes that the only long-term solution is for the NIDDK to invest more dollars in clinical research to provide the funding necessary to recruit, train and retain talented research investigators. To that end, the Working Group set forth the following strategies:

A1. STRATEGY: To give trainees intensive exposure to the broad scientific concepts underlying their chosen fields of interest in an effort to motivate them to remain in active research for their entire career. Often coordinated programs that mix didactic and laboratory experiences can best achieve this over the course of several years.

A2. STRATEGY: To expand patient-oriented research on health disparities in all segments of the population, thereby recruiting and training a cadre of investigators and support staff capable of attracting volunteers from minority populations.

A3. STRATEGY: To identify talented young people early in their educational careers who are members of underrepresented groups and nurtured them throughout their education, both intellectually and financially. This can be accomplished through opportunities for clinical research, including pilot grants, new and innovative approaches , and given every opportunity to develop the interests and skills required for a career in research. The Institute must seek out and remove barriers at any and all stages in the career tracks of such individuals.

A4. STRATEGY: To advocate for more favorable paylines, with special emphasis and high priority in order to encourage the interest of investigators from outside traditional biology in problems related to the NIDDK's areas of responsibility, including material scientists, physicists, mathematicians, bioengineers.

A5. STRATEGY: To establish a task force or working group to address ways to aid new investigators to establish their own, independent research programs. The NIDDK already is committed to monitoring the numbers of new, first-time investigators receiving research grants to help ensure that their numbers do not decline.

A6. STRATEGY: To identify emerging new technologies at an early stage and ensure that access to them by NIDDK-supported investigators is facilitated by supporting research training opportunities that are timely and appropriate.

OBJECTIVES

INFRASTRUCTURAL NEEDS

A. ANIMAL MODELS

OBJECTIVE: Identify/establish and characterize accurate animal models for the study of diseases within the Institute's portfolio.

INSIGHT: Over the past few ears, tremendous progress has been made in developing new animal models for the study of disease. These models have led to important new insights into the mechanisms which lead to the development of certain diseases, as well as insights into the mechanisms of disease progression. However, opportunities for greater progress has been limited by numerous factors, including the expense associated with such studies, the technologies required to study and characterize animal models are limited, and not all aspects of a given disease may be accurately mimicked in a particular animal model.

B. NEW TECHNOLOGIES

B1. OBJECTIVE: Identify new technologies critical to the advancement of the NIDDK research effort.

B2. OBJECTIVE: Establish new mechanisms for the development and shared use of novel technologies needed by the researchers supported by the NIDDK.

INSIGHT: There have been major advances in a variety of new technologies capable of influencing positively the research conducted and supported by the NIDDK. Application of these technologies is often limited due to the high costs associated with such technologies and by control of the technology by industry. For example, DNA chips and other high through-put screening technologies could greatly enhance efforts to identify the genes responsible for many of the diseases within the research mission of the NIDDK. Development of the specialized chips for such purposes has substantial costs, often beyond those of an academic investigator, and often requires the transfer of intellectual property rights. In some cases, a technology required to solve a particular problem, or question posed by an investigator, may not exist.

C. BIOINFORMATICS

OBJECTIVE: Develop mechanisms for the generation and shared use of databases housing certain kinds of information generated by the NIDDK investigative community.

INSIGHT: In order to study complex diseases, it is necessary to integrate enormous amounts of information. For example, a major outcome of the progress in obtaining genomic sequences from vertebrate and invertebrate organisms is the ability to elucidate gene function(s). A direct corollary is the ability to identify particular disease gene. With the accumulation of large amounts of data has come the development of relational databases devoted to providing a curated source of information about genes, including sequences, mutations, protein products, and relationship to genes from other organisms. The development of databases that relate structure with function and provide interactive links to proteins with their sequences has opened up the prospect for making rapid progress in understanding gene function and the development of a disease. This revolution in bioinformatics has permitted investigators to create databases in which information on a gene, or its expressed protein, can be sorted and stored in numerous ways, such as by family, function or relationship to a particular pathway. Thus it becomes possible to fully catalog a given protein, gene, tissue or organism, with links to anatomy function, and disease.

D. CLINICAL RESEARCH NEEDS

*Note: Objectives may be overlapping and similar to those objective outlined in the Prevention and Treatment Section.

D1. OBJECTIVE: Increase and enhance the clinical research capacity of the NIDDK investigative community.

D2. OBJECTIVE: Assist the NIDDK investigative community to conduct clinical research to improve the quality of life for those afflicted with disease, especially ethnic and racial minorities.

D3. OBJECTIVE: Position the NIDDK investigative community to compete successfully for clinical research support.

D4. OBJECTIVE: Identify, recruit and retain more research volunteers.

INSIGHT: As discussed in previous sections, clinical research represents the critical interface between the bench and the bedside, with information flowing in both directions. At present, many types of clinical research are limited due to the costs associated with conducting this type of research, lack of training and expertise of investigators, and difficulty in establishing the needs for bench to bedside transition. In addition, identification and recruitment of potential research volunteers is often a major obstacle. Moreover, once these individuals have been identified, there are sometimes barriers to their retention in clinical research studies.

IMPLEMENTATION STRATEGIES

A. STRATEGIES TO STRENGTHEN CONDUCT OF RESEARCH ON ANIMAL MODELS

The Working Groups have identified the following strategies to strengthen the conduct of research on animal models:

A1. STRATEGY: Ensure investment for research on small and large animal models.

A2. STRATEGY: Encourage the development of animal models that more faithfully mimic human disease processes.

A3. STRATEGY: Establish mechanisms, such as innovative models for cooperative consortia, for facilitating specialized centers to house, breed and characterize genetically modified animals.

A4. STRATEGY: Encourage development of new methods for characterization of animal models to determine the extent to which they mimic human disease.

A5. STRATEGY: Generate mechanisms for storing and sharing information generated from the study of animal models.

B. STRATEGIES FOR THE EFFECTIVE DEVELOPMENT AND SHARED USE OF NOVEL TECHNOLOGIES

The Working Groups have identified the following strategies:

B1. STRATEGY: Ensure--in cooperation with trans-NIH efforts--investment in technology development.

B2. STRATEGY: Generate clear expectations for shared use of all novel technologies developed by the NIDDK investigative community.

C. STRATEGIES FOR THE EFFECTIVE DEVELOPMENT AND SHARED USE OF DATABASES

In addition to the strategies relevant to bioinformatics discussed in previous sections, the Working Groups have identified the following strategies:

C1. STRATEGY: Develop programs to improve availability of annotated sequence information.

C2. STRATEGY: Develop appropriate informatics tools and databases.

C3. STRATEGY: Ensure that investigative communities have access to training in the development and use of informatic tools.

D. STRATEGIES TO ENHANCE CLINICAL RESEARCH

Strategies to enhance clinical research infrastructure were also discussed in the Prevention and Treatment of Disease section, and may therefore appear more than once.

D1. STRATEGY: Extend to the NIDDK investigative community expertise in clinical trial design and analysis found within the Institute.

D2. STRATEGY: Ensure fair and effective reviews of extramural applications for support of clinical research.

 D3. STRATEGY: Enhance partnerships with academic health centers, foundations, and the pharmaceutical and managed care industries to increase clinical research.

D4. STRATEGY: Expand interactions with NIDDK-supported Centers of Excellence, as well as NIH-supported General Clinical Research Centers.

D5. STRATEGY: Expand the use of telemedicine and other information technologies to link the research communities.

D6. STRATEGY: Enhance dissemination of information to the public on the importance and results of clinical research.

D7. STRATEGY: Enhance current on-line directories to identify clinical studies conducted and supported by the NIH.

 SIDEBARS

RESEARCH INFRASTRUCTURE

BIOINFORMATICS

Recent advances in molecular biology, coupled with recent advances in the technologies used to generate, analyze, and store data, have allowed for the sequencing of large portions of the genomes of several species. To understand the function of newly identified genes, individual scientists generally focus on specific molecules, signaling pathways, cells, tissues, or organs. Ultimately, however, all of this information must be combined to form a comprehensive picture of normal cellular activities and how they are altered in disease states. Increasingly, the tools of information science are being used to facilitate the careful storage, organization, and indexing of collected data necessary for this integration. The emerging filed of study is referred to as bioinformatics.

Bioinformatics deals with tasks such as creation and maintenance of biological databases, such as nucleic acid and proteins sequence, three dimensional protein structures, and characteristics of animal models, as well as developing an interface whereby investigators can both access existing information and submit new entries. The actual process of analyzing sequence information is referred to as computational biology. This process involves multiple steps, including the identification of a gene and the DNA sequence; predicting the structure and function of the protein produced by the gene; clustering of these proteins into "families" of related nucleic acid sequences; and aligning similar proteins based on their DNA sequence to study evolutionary relationships.

The NIDDK is undertaking, or has planned for the near future, initiatives to obtain genomic and functional information on a spectrum of genes and their expressed protein products in a number of disease areas within the NIDDK research mission. For example, the NIDDK has taken the lead on a trans-NIH initiative to map the zebrafish genome. The zebrafish, because of its short reproductive cycle and its transparent and easily accessible embryos, has recently emerged as an important system for studying events during embryonic development. This system has broad applicability to many of the NIDDK research programs, as well as to other Institutes at the NIH.

Goals of the planned Diabetes Genome Anatomy Project (DGAP) are to identify and characterize all the genes implicated in both type 1 and type 2 diabetes and its complications, followed by complete characterization of the gene products. Emphasis will be placed on using the information generated to develop new approaches to diagnostics and therapeutics and to better understand the diabetes disease process.

An important component of each of these initiatives is the development of an integrated database to collectively house all information generated. For example, data will be collected and stored on newly identified genes, expressed protein products, and the position of genes in the maps of whole genomes. Each database will be open and easily accessible to the research community, as well as interactive so that input from the community may be obtained and incorporated via frequent updates. External advisors from the user communities, as well as from the broader bioinformatics and genomics communities, will be consulted to provide constant input and advice. Ultimately, it is the hope of the NIDDK that such databases will provide a resource for investigators for use in the development of new research assays, for identification of potential therapeutic targets relevant to the many diseases within our research mission, provide points for departure for new research studies, and expedite research progress by disseminating newly emerging information as it develops.

MOUSE MODELS FOR THE STUDY OF HUMAN DISEASE

Animal models provide an essential tool for understanding health and disease in humans and for evaluating potential interventions and therapeutics. Animal models make it possible to conduct studies at the molecular, cellular, and tissue level that would not be possible in humans, and can help answer questions raised by human studies. The mouse is an excellent laboratory model for the study of normal cell function and can provide excellent models of human disease.

Mice and humans share many of the same fundamental biological and behavioral processes and have extensive similarities at the molecular, cellular and tissue levels. Mice are also readily susceptible to genetic manipulation. Therefore, mice are expected to prove particularly useful for dissecting the interactions involved in complex genetic traits, where gene action is modified by the behavior of other genes or by environmental factors. Learning the full genetic make-up of the mouse will enable the comparison of genetic material among mouse, humans and other species. This will greatly expedite advances in many avenues of research, including the discovery of new genes, the assessment of predisposition to a particular disease, predicting responses to environmental agents and drugs, and designing new interventions and therapeutics.

Program Initiatives

The NIDDK is participating in a number of strategies to exploit fully mouse models in order to accelerate the emergence of new understandings in health and disease. For example, the NIDDK is participating in the Trans-NIH Mouse Initiative, launched in October 1999. The goal of this initiative is to decipher the full genome, or genetic makeup, of the mouse by mapping the mouse's 21 chromosomes and sequencing the DNA in the mouse genome.

Another initiative will target mouse models of kidney disease and will invite investigators with expertise in many areas to form a consortium to accelerate the pace at which accurate and reproducible models of kidney disease are developed and made available to the research community. Polycystic kidney disease and kidney disease of diabetes mellitus will be areas of special focus. Through the formation of a consortium, investigators will have access to resources, information, technologies, ideas, and expertise usually beyond the scope of any one researcher or research team. As researchers develop and validate models, the NIDDK will provide mechanisms to disseminate the models and data collected to the research community.

A parallel initiative will solicit applications to establish national centers for the purpose of fully characterizing other models useful for understanding diabetes, its complications, obesity, and other related metabolic diseases and conditions. In some animal models, a gene (or genes) is "knocked out" so that researchers can study what happens in its absence and how this gene may contribute to or inhibit disease. These facilities would provide a range of standardized procedures to characterize the physiologic, anatomic, or pathologic alterations that may occur in these, as well as other types of models. This type of analysis is referred to as phenotyping.

Another initiative will encourage the development of commercially available miniaturized assays to measure metabolic and physiologic function. These specialized assays would be for use in the characterization of genetically engineered mouse models, or for use in very small volumes of human tissues.

Research Advances

The NIDDK also reported a number of research advances this year that demonstrate the importance of mouse models in defining and treating diseases within the NIDDK research mission. For example, in an effort to dissect out the role of tissue specific insulin signals in the development of diabetes, NIDDK investigators have succeeded in generating a mouse model in which the insulin receptor from pancreatic beta cells is deleted. Animals lacking these receptors demonstrate a defect early in insulin secretion, and as they age, they have a progressive inability to respond to glucose. By six months of age, they are glucose intolerant, a major feature of type 2 diabetes in humans. Insulin levels in the pancreas also seem to decline with age in this model, although agents other than glucose seem to be able to stimulate normal release of insulin. This progressive loss of insulin secretion in response to glucose, but not to other agents, is another hallmark of progression to type 2 diabetes in humans. This work points to receptors on the beta cell as important sites where impairment of insulin signaling can lead to pancreatic dysfunction and to the development of diabetes.

NIDDK intramural researchers have demonstrated the prevention of lysosomal storage in a mouse model of Tay Sachs, a disease in which there is abnormal accumulation of a specific type of lipid in cells, resulting in organ and brain damage. The agent tested in this mouse model acts by blocking a particular step in the synthesis of glucose-based lipids and could potentially be used to treat all storage diseases with defects in the degradation of these lipids. To further test this theory, investigators then created a mouse model of substrate deprivation for another lipid storage disease. This model had simultaneous defects in synthesis and degradation of the lipid, mimicking the effect of the agent described above. These mice no longer accumulated the lipid, had a much longer lifespan, and had improved neurologic function, demonstrating the effectiveness of such a treatment.

The NIDDK supports a number of other individual projects that directly involve the derivation or study of mice that develop specific diseases. The Institute is committed to supporting in the future coordinated, collaborative efforts to produce highly accurate mouse models of human diseases within its research mission. The NIDDK is encouraging studies for the early design, derivation, characterization, and validation phases of model building, and will ensure that the models and the data relevant to them are readily available to the research community for further investigation or application.

CRITICAL TECHNOLOGIES

The tremendous acceleration in the pace of scientific discovery over the last decade, coupled with development of many new high-throughput technologies, has created an era of unparalleled opportunity to uncover the causes of disease and identify effective therapies. In particular, the Human Genome Project effort has generated an explosion of data and potential tools that will aid research in virtually all fields of medicine. The recent development of genome-wide expression profiling allows for a comprehensive high-throughput screening of the effects of an insult, whether it be genetic or environmental, on gene expression in tissues and specific cell populations. These techniques may aid in determining the function of a newly discovered gene, discovering new ways to identify individuals at risk for developing disease, tracking disease progression, and developing therapeutics for patients with disease.

Three technologies the NIDDK believes are critical to accomplishing these goals, and intends to actively pursue through the development of Biotechnology Centers, are cDNA microarrays, oligonucleotide chips, and Serial Analysis of Gene Expression, or SAGE. The development of such advanced technologies requires the collaboration of investigators with expertise in many fields, such as molecular biology, robotics, bioinformatics, and statistics. As costs associated with these technologies are high, the NIDDK proposes to support key aspects of infrastructure, including the development and maintenance of appropriate databases and special equipment.

Imaging technology has also advanced rapidly in recent years. New imaging techniques, including relatively noninvasive techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), and absorption or fluorescence spectroscopy, represent a revolution in research capabilities. It is now possible to image small or deep structures that have until now been impossible. The NIDDK has undertaken a number of initiatives to capitalize on these technological advances.

The NIDDK has two initiatives designed to stimulate research on the development of novel imaging methods to aid in the design of clinical interventions. The first in is polycystic kidney disease (PKD), a serious and costly disease. Although there have been important advances in the molecular basis of PKD, clinical interventions to slow destruction of kidney function are needed. Studies are beginning to test whether imaging techniques can provide accurate and reproducible markers of disease progression by monitoring changes in cyst size.

A second initiative on imaging focuses on the pancreatic beta cell. It is designed to stimulate the development of techniques to the ability to image, or otherwise noninvasively detect, beta cell mass, function, and evidence of inflammation. It is anticipated that research under this initiative will contribute to eventual development of a clinical exam that could be used for monitoring disease progression in response to therapy in diabetic patients and in individuals at high risk for developing diabetes. Also, type 1 diabetes is now being successfully treated using pancreas transplantation, and researchers may soon be able to introduce healthy, functioning isolated pancreatic islets into patients. In the course of developing this technique, it would be of great clinical benefit to the patient to be able to identify the location, number, viability, growth, and function of these grafts and to be able to monitor their response to immune modulating therapies. Because of the highly technical nature of this work, collaboration between researchers in the fields of imaging, beta cell biology, diabetology, chemistry, and engineering will be necessary.

CLINICAL RESEARCH REPOSITORIES

The NIDDK is formulating an initiative to enhance clinical research within the Institute by developing a resource repository system that will be accessible to all of the NIH research community. The NIDDK currently supports a variety of clinical trials that separately collect and store enormous amounts of data, as well as patient samples such as serum, tissue, urine, and DNA and RNA. Collecting and storing such data and samples separately is expensive, often difficult to monitor, and leads to duplication of efforts. The goal of this initiative will be to create a common repository in which the many types of data and specimens collected would be stored, monitored, and distributed to the research community to facilitate future research studies. A major strength of this resource repository will be the availability of correlative clinical data, such as demographic, clinical, and outcome data.

A network of cooperating institutions will be assembled by the NIDDK and will work together to meet the goals of this initiative. The NIDDK will also constitute a coordinating committee to govern the repository as well to ensure smooth interactions among the cooperating organizations. An outside scientific review group will be assembled in consultation with the coordinating committee to review all requests for use of the resources.

Operation of such a repository, including data management, would also be subject to oversight by an Institutional Review Board. The Board would review and approve a research protocol specifying the conditions under which data and specimens may be accepted and shared, thereby ensuring patient privacy and maintaining confidentiality of data. This Board would also review and approve sample collection protocols and informed consent documents for future distribution of samples.

Human specimens are a resource to test hypotheses on normal biology as well as on disease processes. Not only will utilization of human specimens allow for the characterization of the molecular mechanisms of disease, but it may clarify potential relationships between diseases as well as complications associated with a particular disease. The use of human specimens will also provide a unique resource for research focused on developing new therapeutic interventions.

APPENDIX 1

Overview of Ongoing Scientific Programs Supported by the NIDDK

What follows are detailed summaries of the major scientific programs supported by each of the NIDDK's scientific operating divisions, including the:

• Division of Diabetes, Endocrinology, and Metabolic Diseases
• Division of Digestive Diseases and Nutrition
• Division of Kidney, Urologic, and Hematologic Diseases

Division of Diabetes, Endocrinology, and Metabolic Diseases

The Division of Diabetes, Endocrinology, and Metabolic Diseases is responsible for extramural programs related to diabetes mellitus and its complications; endocrinology and a variety of endocrine disorders; and metabolism and metabolic diseases, including cystic fibrosis.

Support for basic and clinical biomedical research, epidemiologic and behavioral studies, and clinical trials is provided through investigator-initiated research grants, program project and center grants, cooperative agreements, contracts, and Small Business Innovative Research awards.

The Division also supports a variety of career development and training awards, as well as a limited number of resource, and research and development contracts. In addition, the division provides leadership in coordinating activities throughout the NIH and various other Federal agencies.

Brief descriptions follow for each of the Division's major program areas.

The Therapeutic Approaches to Diabetes Mellitus Program encompasses studies of therapeutic approaches to achieving euglycemia. Specific areas of support include: 1) studies on drug development; 2) transplantation of pancreas, or pancreatic endocrine cells (islets or $-cells); 3) glucose sensors (including in combination with insulin delivery systems to provide a closed-loop system); 4) cellular therapy (including gene therapy approaches) that are being proposed to treat or prevent either type 1 or type 2 diabetes; 5) studies in cell culture to bioengineer or genetically manipulate cells with the intent to produce an insulin-secreting cell or a glucose-responsive insulin-secreting cell for the eventual treatment of diabetes; and 6) creation of animal models for therapeutic trials.

The Type 1 Diabetes Clinical Trials Program supports large, multi-center clinical trials conducted under cooperative agreements or contracts. The focus of the Diabetes Prevention Trial Type-1 (DPT-1) is to determine whether it is possible to prevent or delay the onset of type 1 diabetes in individuals determined to be at immunologic, genetic, and/or metabolic risk. The program also supports the Epidemiology of Diabetes Interventions and Complications study, an epidemiologic follow-up study of the subjects previously enrolled in the Diabetes Control and Complications Trial.

The Type 2 Diabetes Clinical Trials Program supports large, multi-center clinical trials conducted under cooperative agreements or contracts. The Diabetes Prevention Program (DPP) is focused on testing lifestyle and pharmacological intervention strategies in individuals at genetic and metabolic risk for developing type 2 diabetes to prevent or delay the onset of this disease.

The Endocrine Pancreas Program focuses on studies on the endocrine cells (alpha, beta, delta, etc.) of the pancreas and islets. Specific areas of research include: 1) cell growth and development or differentiation of these cells and identification of their growth/differentiation factors; 2) identification of stem cells giving rise to endocrine cells of the pancreas; 3) studies on regeneration, storage, preservation and growth of pancreatic endocrine cells and islets; 4) studies of islet structure; and 5) studies of the function and regulation of these cells, including insulin and other hormone synthesis and secretion.

The Insulin Receptor Program encompasses studies of cell biology, structure, function and action of the insulin receptor. Specific areas of support include: 1) molecular analysis of ligand binding to receptor; 2) activation of the tyrosine kinase; 3) subsequent insulin receptor function in signal transduction by serving as a platform for the attachment of downstream signaling molecules involved in insulin action; 4) the Insulin Receptor Signaling proteins (IRS)-1,2,3,4, and other proteins containing Src Homology Domains (e.g., SH2).; 5) signaling cross-talk with other related and receptor signaling pathways; and 6) regulation of gene expression.

The Insulin Resistance Program supports research on: 1) the role of insulin resistance in the pathogenesis of type 2 diabetes mellitus; 2) the relationship between insulin resistance and obesity; 3) the relationship between insulin resistance and physical inactivity; 4) new methods to measure peripheral insulin resistance; 5) the molecular basis of decreased sensitivity to insulin; 6) insulin receptor desensitization; 7) uncoupling of receptor activation to downstream events; and 8) animal models of insulin resistance.

The Genetics of Diabetes Program endeavors to identify genes that contribute to type1 and type 2 diabetes mellitus. Specific areas of support include: 1) studies using animal models to identify diabetes genes; 2) studies using quantitative statistical methods to identify diabetes genes in human populations; and 3) development of genetic resources, patient samples, and methods for studying genetic linkage for diabetes.

The Complications Genetics Program is focused on elucidation of the genes which increase an individual's susceptibility to the complications of diabetes. This program supports research related to the discovery of genes involved in the basic process/mechanisms of complications. These mechanisms underlie the involvement of multiple organs including the kidneys, nervous system, eye, and vasculature.

The Complications of Diabetes Program encompasses research related to classical diabetic complications and the effect of diabetes on any organ system. This includes, but is not limited to, the kidney, eye, nervous system, vascular system, and reproductive system. Effects include acute ketoacidosis, as well as the chronic complications of diabetes. Research examines the molecular and cellular mechanisms by which hyperglycemia mediates its adverse effects and the interrelationships among the mechanisms potentially involved in the pathogenesis of complications, including increased polyol pathway flux, alterations of intracellular redox state, oxidative stress, glycation of structural and functional proteins, altered expression of growth factors, enhanced activity of protein kinase C, impaired synthesis of nitric oxide and vasoactive prostacyclins, and altered metabolism of fatty acids.

The Hypoglycemia Program encompasses studies on the pathogenesis, prevention, treatment and sequelae of hypoglycemia (low blood glucose) in both type 1 and type 2 diabetes. Specific areas of research include: 1) studies to identify the biologic systems involved in recognition and response to hypoglycemia; 2) studies designed to examine the interplay of counter regulatory endocrine responses; and 3) studies designed to ascertain the regulatory mechanisms for glucose homeostasis and the cells involved in this regulation.

The Autoimmunity/Viral Etiology of Endocrine Disease Program emphasizes support of investigator-initiated basic and clinical research on the etiology and pathogenesis of type 1 diabetes and autoimmune thyroid disease. Specific areas of support include: 1) the autoimmune basis of the disease; 2) viral and other environmental agents with potential roles in the etiology and pathogenesis of disease; and 3) studies using animal models to further our understanding of type 1 diabetes or autoimmune thyroid disease.

The Type 1 Diabetes Epidemiology Research Program focuses on the distribution and determinants of type 1 diabetes and its complications in populations, including community-based groups and large patient populations. Specific areas of research include: 1) epidemiologic studies on the genetic and environmental factors that determine type 1 diabetes; 2) geographic and temporal variations in the disease; 3) variations in disease frequency by race, socioeconomic status, metabolic factors, and other determinants; 4) studies on the etiology of diabetes, including identification of risk factors that determine susceptibility to diabetes, and variations in the distribution of risk factors within populations and within individuals; 5) research on the etiology and pathogenesis of diabetes complications in well-defined populations; and 6) the genetic, lifestyle, and environmental factors that predispose people with diabetes to complications.

Special emphasis is placed on epidemiologic studies of U.S. minority populations in which the prevalence and severity of diabetes and its complications is substantially elevated.

The Type 2 Diabetes Epidemiology Research Program focuses on the distribution and determinants of type 2 diabetes, gestational diabetes, and complications of diabetes in populations, including community-based groups and large patient populations. Specific areas of research include: 1) epidemiologic studies on the genetic and environmental factors that determine type 2 diabetes; 2) geographic and temporal variations in the disease; variations in disease frequency by race, socioeconomic status, metabolic factors, and other determinants; 3) studies on the etiology of diabetes, including identification of risk factors that determine susceptibility to diabetes, and variations in the distribution of risk factors within populations and within individuals; 4) research on the etiology and pathogenesis of diabetes complications in well-defined populations; and 5) the genetic, lifestyle, and environmental factors that predispose people with diabetes to complications.

Special emphasis is placed on studies of U.S. minority populations in which the prevalence and severity of type 2 diabetes and its complications is substantially elevated.

The National Diabetes Data Group (NDDG) serves as the major Federal focus for the collection, analysis, and dissemination of data on diabetes and its complications. Drawing on the expertise of the research, medical, and lay communities, the NDDG initiates efforts to: 1) define the data needed to address the scientific and public health issues in diabetes; 2) foster and coordinate the collection of these data from multiple sources; 3) identify important data sources on diabetes, and analyze and promulgate the results of these analyses to the scientific and lay public; 4) promote the timely availability of reliable data to scientific, medical, and public organizations and individuals; 5) modify data reporting systems to identify and categorize more appropriately the medical and socioeconomic impact of diabetes; 6) promote the standardization of data collection and terminology in clinical and epidemiologic research; and 7) stimulate development of new investigator-initiated research programs in diabetes epidemiology.

The Diabetes Mellitus Interagency Coordinating Committee (DMICC), established in 1974 and chaired by the Director, Division of Diabetes, Endocrinology and Metabolism, includes representatives from all Federal departments and agencies whose programs involve health functions and responsibilities relevant to diabetes mellitus and its complications. Functions of the DMICC are: 1) coordinating research activities of the NIH and those activities of other Federal programs that are related to diabetes mellitus and its complications; 2) ensuring the adequacy and soundness of these activities; and 3) providing a forum for communication and exchange of information necessary to maintain coordination of these activities.

The National Diabetes Education Program (NDEP), co-sponsored by the NIDDK and the Centers for Disease Control and Prevention (CDC), is focused on improving the treatment and outcomes for people with diabetes, promoting early diagnosis, and ultimately preventing the onset of diabetes. The goal of the program is to reduce the morbidity and mortality associated with diabetes through public awareness and education activities targeted to the general public, people with diabetes and their families, health care providers, and policy makers and payers. These activities are designed to: 1) increase public awareness that diabetes is a serious, common, costly, and controllable disease that has recognizable symptoms and risk factors; 2) encourage people with diabetes, their families, and their social support systems to take diabetes seriously and to improve practice of self-management behaviors; and 3) alert health care providers to the seriousness of diabetes, effective strategies for its control, and the importance of a team care approach to helping patients manage the disease. Toward these ends, the NDEP is developing partnerships with organizations concerned about diabetes and the health care of its constituents.

The Diabetes Centers Program administers two types of center awards, the Diabetes Endocrinology Research Centers (DERC) and the Diabetes Research and Training Centers (DRTC). An existing base of high quality diabetes-related research is a primary requirement for establishment of either type of center. While not directly funding major research projects, both types of center grants provide core resources to integrate, coordinate, and foster the interdisciplinary cooperation of a group of established investigators conducting research in diabetes and related areas of endocrinology and metabolism. The two types of centers differ in that the DERC focuses entirely on biomedical research while the DRTC has an added component in training and translation.

The Behavioral Research Program encompasses individual, family, and community-based strategies aimed at prevention of diabetes and its complications through lifestyle modifications, education, and other behavioral interventions. Particular emphasis is placed on development of culturally sensitive, lifestyle interventions to prevent or treat diabetes in diverse high-risk populations, including African-Americans, Hispanic Americans, and Native Americans. Specific areas of research include: 1) the link between behavior and physical health as it relates to diabetes and complications; 2) approaches to improving health-related behaviors and to enhancing diabetes self-management; and 3) other aspects of diabetes care.

The Regulation of Energy Balance and Body Composition Program encompasses research on regulation of body composition by the hypothalamus and circulating factors. Specific areas of support include: 1) endocrinology of body composition, including interactions between nutrition, exercise, and anabolic hormones; 2) neuropeptides and their receptors involved in regulatory pathways controlling feeding behavior, satiety, and energy expenditure; 3) interactions between hypothalamic-pituitary adrenal axis and peripheral metabolic signals (for example, insulin, leptin, glucocorticoids); 4) hormones and cytokines involved in wasting syndromes (cancer, AIDS); 5) endocrine regulation of energy balance via uncoupling proteins; and 6) hypothalamic integration of peripheral endocrine and metabolic signals.

The Adipocyte Biology Research Program encompasses research that addresses the development and physiology of the adipocyte cell. Specific areas of support include: 1) studies on the properties of transcription factors that regulate adipocyte differentiation; 2) research on the consequences of insulin action on adipocyte physiology; and 3) use of animal and tissue culture models to understand adipocyte biology.

The Glucose Transport Program seeks to develop a sound base of fundamental science on all aspects of glucose transport in health and disease, especially as it relates to glucose homeostasis in diabetes and obesity. Specific areas of support include: 1) kinetics and regulation of glucose uptake in muscle, liver, heart, gut, pancreas, kidney, etc; 2) regulation and mechanism of glucose transporter (GLUT) storage, translocation to the membrane, and gene expression by insulin and other hormones, glucose, diet, exercise, and metabolic state (fasting, obesity); 3) structure of glucose transporter; and 4) kinetic and structural studies of the transport proteins and/or membrane channels of other nutrients, such as amino acids, ions and metals.

The Glucose Metabolism Program emphasizes basic and clinical studies of glucose and glycogen metabolism, which will lead to the development of effective treatments for diabetes, glycogen storage disease, obesity, burn injury, sepsis and trauma, and other metabolic diseases. Specific areas of support include: 1) the measurement of flux through pathways of glucose utilization, production, and storage; 2) the mechanism of neural and hormonal regulation of glucose homeostasis; 3) the effects of diet and exercise on glucose metabolism; 4) mathematical modeling of whole body or organ glucose metabolism; 5) interactions between carbohydrate, lipid, and amino acid metabolism in health and disease; and 6) pancreatic hormone regulation of non-glycolytic enzymes, especially those in the TCA cycle.

The Lipid Metabolism Program emphasizes basic and clinical studies of the metabolism of fatty acid, triacylglycerols, cholesterol, and related molecules, which will lead to the development of effective treatments for diabetes, obesity, hypertriglyceridemia, hypercholesterolemia, burn injury, sepsis, and other metabolic diseases. Specific areas of support include: 1) flux and regulation of oxidation, storage, and remodeling of dietary lipids in health and disease, and the effects of diet and exercise; 2) regulation of lipid esterification, hormone-sensitive lipases, and phospholipid metabolism; 3) membrane transport and movement of lipids within the cell, or between organs (binding proteins, carnitine transferases); 4) lipid-protein interactions; 5) metabolism of bioactive lipids and their precursors; and 6) lipid peroxidation, especially associated with disease.

The Protein Metabolism Program encompasses basic and clinical studies of protein, peptide, and amino acid metabolism, as well as studies of purified protein structure, kinetics, function, and enzyme reaction mechanism. Hormone regulation, effects of diet and exercise, and the pathology associated with metabolic diseases are of special interest. Specific areas of support include: 1) studies of flux or regulation of total protein synthesis and turnover in health and disease, including investigations of the specific enzymes of protein and amino acid metabolism; 2) amino acid and peptide membrane transport; 3) uptake, metabolism, and synthesis of specific amino acids; 4) regulation of urea production and nitrogen balance; 5) role of cofactors, vitamins, and minerals in metabolism and enzyme action; and 6) structure of specific classes of enzymes (redox, phosphate transfer, etc.) elucidated by x-ray, NMR, or electron microscopy.

The Steroid Metabolism Program emphasizes basic research into the biochemistry, molecular biology, genetics, metabolism, and biological function of steroids and similar molecules derived from cholesterol, including sex steroids and other hormones (glucocorticoids, mineralocorticoids), retinoids, cardiac glycosides, prostaglandins, eicosanoids, and bile acids. Specific areas of support include: 1) the structure and reaction mechanisms of enzymes and enzyme-substrate complexes in steroidogenesis and steroid interconversion pathways; 2) cholesterol activation for steroidogenesis, including cholesterol esterase and intramitochondrial translocation of cholesterol; 3) structure, function, and reaction mechanism of the p450 class of enzymes; 4) estrogens and androgens in development; and 5) structure and function of the mitochondrial cytochromes.

The Inborn Errors of Metabolism Program encompasses research in the pathophysiology and treatment of genetic metabolic diseases. Specific areas of support include: 1) studies of etiology, pathogenesis, prevention, diagnosis, pathophysiology, and treatment of these diseases; 2) characterization of the genes, gene defects, and regulatory alterations that are the underlying causes of these diseases; 3) studies of the mutant enzyme and its effect on the structure and function of the protein; 4) the development of animal models for genetic disease; 5) development and testing of dietary, pharmacologic, and enzyme replacement therapies; and 6) development of stem cell transplantation, both prenatally and postnatally, as a treatment for metabolic diseases.

The Cystic Fibrosis Research Program encompasses fundamental and clinical studies of pathophysiology and development of new therapies. Specific areas of support include: 1) the cystic fibrosis gene, its protein product CFTR, and the molecular mechanisms by which mutations cause disease; 2) roles of normal and mutant CFTR in transport and other cellular processes; 3) genotype/phenotype studies; 4) mechanisms underlying the lung inflammation and infection of cystic fibrosis; 5) pancreatic insufficiency, malnutrition and growth failure, impaired fertility, liver disease, and other complications of cystic fibrosis; 6) development of new therapies by modulating or compensating for the functional defects in mutant CFTR, stabilizing mutant CFTR, and enhancing its targeting and integration into the cell membrane, and safe and effective methods for gene therapy; 7) development of animal or cell models; and 8) evaluation of therapeutic interventions in cystic fibrosis in clinical studies or animal models.

The Gene Therapy Program encompasses research aimed at developing basic and applied gene therapy for genetic metabolic diseases. Specific areas of support include: 1) pilot and feasibility studies (R21) to improve gene delivery systems; 2) studies of the basic science of AAV, adenovirus, retrovirus, and lentivirus vectors; 3) studies of non-viral methods of gene transfer such as liposomes or DNA-conjugates; 4) studies to target gene delivery to specific cell types; and 5) gene therapy of stem cells to treat a genetic metabolic disease.

The Gene Therapy and Cystic Fibrosis Centers Program supports three types of centers: Gene Therapy Centers (P30); Cystic Fibrosis Research Center (P30); and Specialized Centers for Cystic Fibrosis Research (P50). Gene Therapy Centers provide shared resources to a group of investigators to facilitate development of gene therapy techniques and to foster multidisciplinary collaboration in the development of clinical trials for the treatment of cystic fibrosis and other genetic metabolic diseases. Cystic Fibrosis Research Centers (P30), and Specialized Centers for Cystic Fibrosis Research (P50) provide resources and support research on many aspects of the pathogenesis and treatment of cystic fibrosis.

The Bone and Mineral Research Program encompasses basic and clinical research on the hormonal regulation of bone and mineral metabolism in health and disease. Specific areas of support include: 1) endocrine aspects of disorders affecting bone, including osteoporosis, Paget's disease, renal osteodystrophy, and hypercalcemia of malignancy; 2) pathogenesis, diagnosis and therapy of parathyroid disorders, including primary or secondary hyperparathyroidism; 3) effects of parathyroid hormone (PTH), parathyroid hormone related protein (PTHrP), calcitonin, vitamin D, estrogen, retinoic acid, growth factors (e.g. IGF-I, etc.), glucocorticoids, thyroid hormone, and other systemic or local-acting hormones and their receptors on bone structure and function; 4) bone active cytokines (e.g. TGF-beta, BMPs, CSF-1) and their role(s) in bone cell biology; 5) studies of calcium homeostasis, absorption, metabolism, and excretion, including the calcium activated receptor (CaR); 6) basic and clinical studies of vitamin D; and 7) bone morphogenesis, including studies of signaling in the regulation of developmental factors involved in bone formation (e.g. hedgehogs, Hox genes).

The Thyroid Research Program is focused on normal thyroid physiology and non-autoimmune thyroid disease, including thyroid neoplasia. Specific areas of support include: 1) physiologic regulation of the expression, processing, and secretion of thyroid hormones; 2) dysfunctional regulation of thyroid hormones that results in disease; 3) studies of the etiology, pathogenesis, diagnosis, and therapy of thyroid disorders; 4) studies on the deiodinase enzymes that convert inactive thyroid hormone to active thyroid hormone; and 5) studies on neural cells that are targets of regulation by and feedback to the thyroid.

The Reproductive Endocrinology Program supports research into the structure and function of gonadotropins, including, LH, FSH, and hCG and their receptors. Specific areas of support include: 1) oligosaccharide modification and its effects on gonadotropin function; 2) the metabolic responses of target tissue (e.g. prostate); 3) studies on the interaction of gonadotropins with their receptors; 4) the physiological effects of the hormones (e.g. menopause, age of onset of menstruation); and 5) the development and study of analogs of gonadotropins.

The Neuroendocrinology Program encompasses research on neuropeptides of the hypothalamus. Specific areas of research support include: 1) physiological response to stress through the hypothalamic-pituitary-adrenal axis; 2) neuropeptides and neuropeptide receptor signaling pathways; 3) gene regulation in the hypothalamus and pituitary gland; 4) diseases of the pituitary, including neoplasia; 5) hypopituitary dwarfism; 6) identification and characterization of novel hypothalamic or pituitary hormones; 7) tissue specific and developmental expression of pituitary and hypothalamic genes; 8) pituitary hormone receptors and actions on target tissues (e.g., GH IGF-1 axis); 9) neuropeptide receptors in diagnosis and treatment of disease; and 10) neuroendocrine-immune interactions.

The Growth Factor/Receptor Structure/Function Program encompasses research on growth factors and cytokines, and their receptors, binding proteins, and inhibitors. Specific areas of support include: 1) regulation of expression of growth factors and their receptors in endocrine cells and tissues; 2) structure/function studies; 3) role of growth factors in endocrine tumor progression; 4) identification of genes that are downstream targets of growth factor receptor activation; 5) modulation of growth factor action by binding proteins; and 6) autocrine and paracrine actions of growth factors and cytokines to regulate cell/tissue growth and function.

The Intracellular Signal Transduction Research Program encompasses research aimed at understanding the structure and function of intracellular signal transducing molecules. Specific areas of support include: 1) intracellular kinases, phosphatases, and anchoring proteins; 2) signaling mechanisms that have altered activity in response to protein phosphorylation, Ca++ and cAMP; 3) approaches to solving the three-dimensional structure of signaling proteins, including crystallography and NMR; 4) functional analysis of these proteins, including comparison of wild-type and naturally occurring or synthetic, mutant proteins or expression of dominant-negative forms of the proteins; 5) microscopic techniques to localize these proteins within cells; 6) the identification of substrates for these signaling proteins; and 7) the analysis of cross-talk among distinct signal transduction pathways.

The G-Protein Coupled Receptors Program encompasses studies on the G-protein coupled receptor superfamily. Specific areas of support include: 1) cell surface, or seven transmembrane domain (7-TM), receptors coupled to GTP-binding (G)-proteins for signal transduction (e.g. beta-adrenergic receptor); 2) receptor structure and function; 3) receptor down-regulation (homologous desensitization); 4) role(s) of mutated receptors in disease; and 5) coupling of signaling through receptors to other membrane-bound effectors and or regulators, such as adenylyl yclase, ion channels, protein phosphatases or kinases, and other receptors. Signal transduction through GPCRs also includes mechanisms of regulation of gene expression through nuclear proteins such as the Cyclic Nucleotide Response Element Binding Protein (CREB) and the CREB binding protein (CBP).

The Nuclear Hormone Gene Superfamily Program encompasses basic and clinical research on members of the steroid hormone superfamily (also known as the nuclear receptor superfamily). The program includes structure/function studies and the role in signal transduction and regulation of gene expression of the steroid hormones (glucocorticoids, mineralocorticoids, progesterone, estrogens, androgens [testosterone], DHEA) and the nuclear receptors, including thyroid hormone, vitamin D, retinoids (RAR, RXR, vitamin A), PPARs, and orphan receptors (LXR, SXR, Nur77, COUP-TF, and others). Topics covered include receptor structure, interaction with cytoplasmic chaperones (e.g. Hsp90, Hsp70, etc.), interaction with ligand, nuclear translocation, binding to hormone response elements, interaction with nuclear accessory proteins (e.g. SRC-1, N-CoR, CBP, histone acetylase/deacetylase, GRIP1, etc.), as well as the basal transcriptional machinery, and regulation of gene expression.

The Transcriptional Regulation of Metabolic Pathways Program emphasizes research aimed at understanding the significance of gene regulation to control of metabolism. Specific areas of support include: 1) the identification and characterization of transcription factors and cis-acting regulatory elements in DNA using structural and functional approaches; 2) identifying mechanisms whereby signal transduction pathways elicit changes in gene expression; and 3) identifying the molecular response to environmental cues, including hormonal stimulation, nutrients, development, and stress.

The Protein Trafficking/Secretion/Processing Research Program encompasses research aimed at understanding the mechanisms that account for the fate of proteins after their initial translation. Specific areas of support include: 1) protein folding; 2) post-translational modifications and the enzymes that catalyze them; 3) the movement of proteins in vesicles from the endoplasmic reticulum (ER) through the golgi and endosomes and their ultimate secretion; 4) mechanisms that account for vesicle formation (pinching-off) and vesicle fusion, which are paramount to understanding trafficking; 5) the movement of proteins in the direction opposite of secretion, including endocytosis and retrograde transport; 6) proteins and small molecules that regulate protein trafficking; and 7) proteasomes, ubiquitin conjugation, and the N-end rule.

The Cytoarchitecture/Matrix Research Program encompasses research into the properties and functions of intracellular and extracellular, filamentous suprastructures that are involved in hormone signaling, and endocrine and metabolic disorders. Specific areas of support include: 1) the extracellular matrix with its constituent collagens, hyaluronans, and proteoglycans; 2) studies of transmembrane proteins that generate adherence through cell-matrix or cell-cell interactions, including integrins, cadherins, selectins, and the Ig superfamily; 3) intracellular structures formed by the actin and intermediate filament networks; and 4) specialized structures formed by these filaments, such as the contractile apparatus of muscle cells.

The Hormone Distribution Program of the NIDDK makes available to the research community human and animal pituitary hormones, antisera to these hormones, and selected other hormonal and biological products. Currently, approximately 180 research materials are distributed through the National Hormone and Pituitary Program. Most of the products are unavailable commercially. Approximately 7,000 individual vials of human and animal hormones and antisera are awarded annually to investigators for immunochemical research. Frozen human pituitaries and rat hypothalami also are available for distribution to scientists attempting to isolate or characterize novel hormones and peptides or variants.

Division of Digestive Diseases and Nutrition

The Division of Digestive Diseases and Nutrition is responsible for managing programs in basic and clinical research, as well as training and career development related to liver and biliary diseases; pancreatic diseases; gastrointestinal disease, including neuroendocrinology, motility, immunology, absorption, and transport in the gastrointestinal tract; nutrient metabolism; obesity; eating disorders; and energy regulation.

Brief descriptions follow for each of the Division's major program areas:

The Liver and Biliary Program supports basic and clinical research on both the normal function and the diseases of the liver and biliary tract. Areas of basic research include: hepatic regeneration, gene therapy, and liver cell injury, fibrosis, and apoptosis; basic and applied studies on liver transplantation, including techniques of preservation and storage; metabolism of bile acids and bilirubin; physiology of bile formation; the control of cholesterol levels in bile; and gallbladder and bile duct function. Areas of disease-oriented research include: cholesterol and pigment gallstones; inborn errors in bile acid metabolism; chronic hepatitis that evolves from autoimmune, viral or alcoholic liver disease; and various liver ailments, such as Wilson's disease, primary biliary cirrhosis, primary sclerosing cholangitis, portal hypertension, hepatic encephalopathy, and Crigler-Najjar syndrome.

The Pancreas Program encourages research into the structure, function, and diseases (excluding cancer and cystic fibrosis) of the exocrine pancreas. Areas of research interest include: hormonal and neural regulation of electrolyte, fluid, and enzyme secretion; receptors for secretagogues; stimulus-secretion coupling mechanisms; gut-islet-acinar interrelations; organization and expression of pancreatic genes; protein synthesis and export; tissue injury, repair, and regeneration; physiology and pathology of trophic responses; neural innervation; transcapillary solute and fluid exchange; duct cell physiology and function; pancreas transplantation, storage, and preservation; imaging of the pancreas; pancreatic insufficiency; and acute and chronic pancreatitis and relevant experimental models.

The Gastrointestinal Transport and Absorption Program supports research on the process of food digestion, and absorption and transport in the gastrointestinal tract, including the synthesis and assembly of digestive enzymes; the transport of water, ions, sugars, amino acids, peptides, lipids, vitamins, and macromolecules; and the formation, structure, and function of chylomicrons. Other areas of research focus on the regulation of gene expression in the gastrointestinal tract; the structure and function of the gut mucosa; the cytoskeletal structure and contractility in brush borders; the growth and differentiation of gastrointestinal cells in normal and disease states; intestinal transplantation, storage, and preservation; and gastrointestinal tissue injury, repair, and regeneration. Also supported are studies on gastrointestinal diseases such as maldigestion and malabsorption syndromes.

The Gastrointestinal Neuroendocrinology Program supports basic and clinical studies on normal and abnormal function of both the enteric nervous system and the elements within the central nervous system that control the enteric nervous system. Neuroendocrine studies supported include: histochemical and neurochemical analyses of the enteric nervous system, electrical properties of enteric ganglia, chemical neurotransmission, neural control of effector function, and extrinsic nervous input. This program places a great deal of emphasis on gastrointestinal hormones and peptides, including their structure, biological actions, structure-activity relationships, receptors, distribution, quantitation, metabolism, release, correlation with physiological events, deficiency, and the role of time variation in the data collected in the above studies. In addition, the program supports studies on disease conditions associated with excessive or inadequate secretion of neuropeptides.

The Gastrointestinal Motility Program focuses on the structure of gastrointestinal muscles, the biochemistry of contractile processes and mechanochemical energy conversion relations between metabolism and contractility in smooth muscle, extrinsic control of digestive tract motility, and the fluid mechanics of gastrointestinal flow. Other studies and areas of interest include the actions of drugs on gastrointestinal motility; intestinal obstruction; and diseases such as irritable bowel syndrome (functional digestive disorders), colonic diverticular disease, swallowing disorders, and gastroesophageal reflux.

The Gastrointestinal Mucosa and Immunology Program focuses on intestinal immunity and inflammation. Areas of interest include ontogeny and differentiation of gut-associated lymphoid tissue; migratory pathways of intestinal lymphoid cells; humoral antibody responses; cell-mediated cytotoxic reactions and the role of cytotoxic effector cells in chronic intestinal inflammation; genetic control of the immune response at the mucosal surface; immune response to enteric antigens in both intestinal and extra-intestinal sites; granulomatous inflammation; lymphokines and cellular immune regulation; leukotriene/prostaglandin effects on intestinal immune responses; T-cell mediated intestinal cell injury; the intestinal mast cell and its role in intestinal inflammation; approaches to optimal mucosal immunoprophylaxis, including viral, bacterial, and parasitic diseases; diseases such as gluten sensitive enteropathy, inflammatory bowel disease, and gastritis; malabsorption syndromes; diarrhea; gastric and duodenal ulcers; disease of the salivary glands (excluding cystic fibrosis); the effects of prostaglandins and other treatment modalities on the gastrointestinal tract; and the possible role of prostaglandins or other agents in the pathogenesis and treatment of digestive diseases.

The Acquired Immunodeficiency Syndrome (AIDS) Program encourages research into the characterization of intestinal injury, mechanisms of maldigestion, and intestinal mucosal functions, as well as hepatic and biliary dysfunction in patients with AIDS or in appropriate animal models. In addition, studies are supported on the mechanisms of nutrient malabsorption, deficiencies of various micronutrients, nutritional management of the wasting syndrome, and other aspects of malnutrition related to AIDS.

The Digestive Diseases Centers Program provides a mechanism for funding shared resources (core facilities) that serve to integrate, coordinate, and foster interdisciplinary cooperation between groups of established investigators who conduct programs of high quality research related to a common theme in digestive disease research. An existing base of high quality digestive disease-related research is a prerequisite for the establishment of a center.

The research emphases of centers in this program presently focus on liver diseases, gastrointestinal motility, absorption and secretion processes, inflammatory bowel disease, structure/function relationships in the gastrointestinal tract, neuropeptides and gut hormones, and gastrointestinal membrane receptors.

Nutritional Sciences Programs

The Nutrient Metabolism Program supports basic and clinical studies related to the requirement, bioavailability, and metabolism of nutrients and other dietary components at the organ, cellular, and subcellular levels in normal and diseased states. Specific areas of research interest include the understanding of the physiologic function and mechanism of action/interaction of nutrients within the body; the effects of environment, heredity, stress, drug use, toxicants, and physical activity on problems of nutrient imbalance and nutrient requirements in health and disease; and specific metabolic considerations relating to alternative forms of nutrient delivery and use, such as total parenteral nutrition. The program also supports research to improve methods of assessing nutritional status in health and disease.

The Obesity and Eating Disorders Program emphasizes research on the biomedical and behavioral aspects of obesity, anorexia nervosa, bulimia nervosa, and binge eating disorder. The goals of such research are to establish a clear understanding of the etiology, prevention, and treatment of these multifaceted conditions. Areas of research interest focus on the physiological, metabolic, psychological, and genetic factors that affect food choices, food intake, eating behavior, appetite, and satiety; the effects of taste, smell, and gastric and humoral (including neurotransmitter) responses in association with dietary intake and subsequent behavior; the physiological and metabolic consequences of weight loss or weight gain; the effect of exercise on appetite and weight control; and individual variability in energy utilization and thermogenesis. The program also encourages investigations on the dietary determinants of the growth and control of adipocyte size and number; the responsiveness of the adipocyte to various metabolic and pharmacologic stimuli; the prevention of obesity and other eating disorders; improved methods of assessing body composition; examination of health risk factors associated with specific degrees of obesity or body composition, and determining the effect of exercise on body composition.

The Obesity Special Projects Program is a new program that will support two major initiatives that began in Fiscal Year 1999. First, is the Study of Health Outcomes of Weight-loss (SHOW) trial, a major multi-center clinical trial that will examine the health benefits and risks of sustained intentional weight loss in obese diabetic patients. The cooperative agreement mechanism will be used to develop the SHOW trial as a collaboration between the NIDDK and the principal investigators selected through an RFA.

In addition, the NIDDK will be the lead Institute for developing a trans-NIH initiative on obesity prevention. This will include support for pilot studies of innovative approaches to prevent obesity in high-risk populations (ranging from children through the elderly). Various mechanisms will likely be used to permit a number of institutes to fund small grants in obesity prevention. This initiative is being coordinated trans-NIH through the NIH Division of Nutrition Research Coordination. The NIDDK grants arising from this initiative will be administered through the Obesity Special Projects Program.

Clinical Nutrition Research Units (CNRUs) comprise the Clinical Nutrition Research Units Program. A CNRU integrates the array of research, educational, and service activities focussed on human nutrition in health and disease. It serves as the focal point for an interdisciplinary approach to clinical nutrition research and for the stimulation of research in areas such as improved nutritional support of acutely and chronically ill persons, assessment of nutritional status, effects of disease states on nutrient needs, and effects of changes in nutritional status on disease.

The Obesity/Nutrition Research Centers (ONRC) Program encourages a multidisciplinary approach to obesity and nutrition research. The goal of an ONRC is to help coordinate and strengthen support for research activities primarily by providing funds for core facilities and associated staff that serve the various projects of the ONRC on a shared basis. This approach has ensured that an ONRC has multiple sponsors, both federal and non-federal, and thereby reduces the likelihood that the ONRC will become unduly dependent on any one source of funds for its continued operation. The specific objectives of an ONRC include efforts to create or strengthen a focus in biomedical research institutions for multidisciplinary research in obesity and nutrition; to develop new knowledge concerning the development, treatment, and prevention of obesity and eating disorders; to understand control and modulation of energy metabolism; to understand and treat disorders associated with abnormalities of energy balance and weight management, such as in anorexia nervosa, AIDS, and cancer; and to strengthen training environments to improve the education of medical students, house staff, practicing physicians, and allied health personnel with regard to these conditions.

The Clinical Trials Program supports clinical trials on Helicobacter pylori; primary biliary cirrhosis; adult and adolescent obesity; inflammatory bowel disease; irritable bowel syndrome; primary sclerosing cholangitis; pancreatitis; nonulcer dyspepsia; prevention, management, and treatment of portal hypertension; recurrent liver disease after transplantation; and hepatitis B and C.

The Epidemiology and Data Systems Program serves as the major Federal focus for the collection, analysis, and dissemination of data on digestive diseases and their complications. The Epidemiology component includes studies that address risk factors for disease occurrence and disease prognosis or natural history. The Data Systems component includes databases and biological repositories that support clinical and epidemiologic studies. A database is a systematic, usually prospective, collection of clinically important information that is stored and retrieved in electronic format. Biological repositories may include genetic, serum, and tissue banks. Both the epidemiology and data systems components relate solely to human studies.

The Research Training and Career Development Program offers research training and career development opportunities in support of the programs of the Division of Digestive Diseases and Nutrition. Four types of National Research Service Awards and one Research Career Development Award are available.

Division of Kidney, Urologic, and Hematologic Diseases

The Division of Kidney, Urologic, and Hematologic Diseases is responsible for oversight and planning of investigative programs designed to address some of the nation's major chronic health problems. Diseases of the kidney and urologic systems and hematologic disorders include conditions that shorten life expectancy for millions of Americans, and produce huge health care costs and substantial disability. The challenge faced by the Division is to insure that the health problems within its scope attract rigorous and innovative investigation, and benefit from the current climate of enhanced scientific opportunity.

It is clear to all observers of the biomedical research arena that we are in the midst of an era of accelerating scientific insights into biological disease processes. To a substantial extent this excitement is enhanced by the anticipation of enormous new insights emerging from a complete catalog of all human genes emerging from the Human Genome Project. But with this excitement comes a growing expectation that in the coming decade this knowledge will yield substantial direct health benefits. This climate of expectation--the responsibility to insure that the promise of new knowledge is realized--gives particular urgency to research planning and oversight processes at both the Institute and Divisional level.

Brief descriptions follow for each of the Division's major program areas:

The Renal Diseases Program supports basic, applied, and clinical research relating to the physiology and pathophysiology of the kidney; structural and functional effects of various hormones and pharmacological agents on metabolism, filtration, transport, and fluid electrolyte dynamics of the kidney; and the effects of drugs and nephrotoxins on the kidney. Other areas of research supported by the program include fundamental and applied research addressing the different forms of glomerulonephritis, the immune and non-immune mechanisms of glomerular injury, tubulointerstitial nephritis, as well as vascular diseases.

The Renal Diseases Program is composed of several specific kidney programs:

The Renal Physiology and Cell Biology Program primarily focuses on the normal development, structure, and function of the kidney, including its biochemistry, metabolism, transport, and fluid electrolyte dynamics. Research is supported on the cellular and subcellular molecular mechanisms involved in transport processes that regulate solute and water excretion, with emphasis on how abnormalities in these transport processes and enzymes may contribute to disease states such as renal stones, hypertension, acid-base abnormalities, and progression of renal disease. Of special interest are studies to elucidate factors that contribute to acute renal failure, which will lead to its prevention or make the disease less severe and, ultimately, speed recovery of kidney function. This program emphasizes applying cellular and molecular biologic techniques to identifying and characterizing growth factors and signal transduction systems and transport systems and respective genes, and to elucidating the structure of genes and their regulation during kidney organogenesis, which may continue to operate in the mature kidney.

The Chronic Renal Diseases Program supports basic and clinical research on renal development and disease, including: 1) causes, pathogenetic mechanisms, and pathophysiology; 2) morphological and functional markers and diagnostic measures; 3) underlying mechanisms leading to progression of renal disease; 4) functional adaptation to progressive nephron loss; 5) natural history of progressive renal diseases; and 6) identification and testing of possible therapeutic interventions to prevent development or halt progression of renal disease.

Research in this program includes the primary glomerulopathies and renal disease from systemic diseases that collectively account for more than 50 percent of all cases of treated end-stage renal disease. Of special interest are studies of inherited diseases such as polycystic kidney disease; congenital kidney disorders; and immune-related glomerular diseases, including IgA nephropathy and the hemolytic uremic syndrome.

The End-Stage Renal Disease Program promotes research to reduce morbidity and mortality from bone, blood, nervous system, metabolic, gastrointestinal, cardiovascular, and endocrine abnormalities in end-stage kidney failure, and to improve the effectiveness of dialysis and transplantation. Of special interest is research on hemodialysis membrane reuse and alternative dialyzer sterilization methods; more efficient, biocompatible membranes; high-flux hemodialysis; and criteria for adequacy of dialysis. We are also interested in research on adequacy, appropriate dialysis dose, and infectious complications in peritoneal dialysis, as well as criteria to identify patients best suited for this therapy. The program seeks to increase graft and patient survival and organ availability through research to improve organ preservation, transplantation across ABO blood groups, HLA cross-matching of donors with recipients, immunosuppression, infection control, and organ donations, especially by African American and other minority groups. Of special interest is research on the causes and prevention of progressive loss of renal function in long-term renal transplants.

The Diabetic Nephropathy Program supports basic research on the pathophysiology and pathogenesis of diabetic nephropathy, natural history studies, and clinical trials through the investigator-initiated R01 mechanism. Fundamental research focuses on the molecular pathogenesis of extracellular matrix expansion and glomerulosclerosis, the role of the renin-angiotension system and growth factors, and the identification of treatments to prevent renal scarring. Of special interest are studies to understand the mechanisms of progressive renal scarring, to identify genes that either protect people from or predispose them to diabetic nephropathy, and to identify early markers of increased risk of the disease.

The Pediatric Nephrology Program supports basic and clinical research directed towards the study of renal diseases that affect children. The majority of diseases leading to end-stage renal failure have their onset in childhood. The program includes research focusing on normal and disordered renal developmental processes, pathogenetic mechanisms and pathophysiology of acute and chronic renal diseases, morphologic and functional markers of renal disease, underlying mechanisms leading to progressive renal disease, functional adaptation to nephron loss, natural history of progressive renal diseases, identification of therapeutic interventions to prevent or slow progression of renal diseases, and testing of these interventions through clinical trials. Areas of particular interest are: 1) inherited and congenital renal diseases such as renal dysplasia, congenital nephrotic syndrome, Alport syndrome, and polycystic kidney disease; 2) molecular, genetic, and cellular aspects of normal and abnormal renal development; 3) primary glomerular disease; 4) renal involvement in systemic disease; 5) diabetic nephropathy; 6) renal artery disease and hypertensive renal disease; 7) renal disease progression; and 8) chronic renal insufficiency, pathophysiology, management, complications, and dialysis and transplantation in the pediatric population.

The Renal Diseases Epidemiology Program supports descriptive and analytic epidemiologic research, including development and analysis of surveillance databases, cross-sectional surveys, prospective observational studies, and case-control studies (for evaluating rare diseases). Key areas of interest include preventing disease; developing early markers of injury; defining risk factors for morbidity and mortality; and increasing evaluation of kidney disease measurements and outcomes in ongoing observational studies. The program is dedicated to increasing the availability of epidemiologic data through both development of new databases and full utilization of existing Federal, state, and private sources of data. The United States Renal Data System (USRDS) is funded under a contract through the Renal Diseases Epidemiology Program of the NIDDK. Mechanisms are currently being developed to enhance the availability of USRDS data to the biomedical and health services research community. In addition, the program is working with the National Center for Health Statistics to develop and analyze the nephrology component measured in the third National Health and Nutrition Examination Survey.

The Urology Program supports basic, applied, and clinical research in prostate and prostate diseases; diseases and disorders of the bladder; male sexual dysfunction; urinary tract infections; urinary tract stone disease; and pediatric urology, including developmental biology of the urinary tract. The Program supports projects on the normal and abnormal function of the genitourinary tract, molecular genetic and molecular biological approaches to the mechanisms of normal and abnormal development and growth of the genitourinary tract, regulation and function of the cells, tissues, and organs of the genitourinary tract; pathophysiology of urological disorders and diseases; and, clinical investigations of urological disorders and therapeutic interventions in these disorders.

A research priority in the Urology Program is the study of chronic inflammatory disorders of the lower urinary tract. The program encourages studies from diverse clinical and basic science disciplines for the investigations of these disorders. Realizing that knowledge about the etiology, pathophysiology, treatment, and epidemiology of these disorders is still limited, an innovative and multidisciplinary approach to investigation is encouraged.

A unique aspect of the Urology Program in the area of prostatic growth and development is the cooperative funding with the National Cancer Institute of prostate research which focus on normal and malignant prostate growth.

The Pediatric Urology Program encourages and supports basic and clinical studies, including: 1) bladder development; 2) urinary tract development; 3) prenatal intervention for urinary tract disorders; 4) vesicoureteral reflux; 5) enuresis; 6) urinary tract and bladder outlet obstruction; 7) congenital abnormalities such as posterior urethral valves and bladder exstrophy; and 8) bladder abnormalities associated with spina bifida.

The Urologic Diseases Epidemiology Program supports descriptive and analytic epidemiology, including development and analysis of surveillance databases, cross-sectional surveys, prospective observational studies, and case-control studies (for evaluating rare diseases). Key areas of interest include preventing disease, developing early markers of injury, defining risk factors for morbidity and mortality, and increasing evaluation of urologic disease measurements and outcomes in ongoing observational studies. The program is dedicated to increasing the availability of epidemiologic data through both development of new databases and full utilization of existing Federal, state, and private sources of data. The program is working with the National Center for Health Statistics to develop and analyze the urology component measured in the third National Health and Nutrition Examination Survey.

The Hematology Program emphasizes a broad approach to understanding the normal and pathologic function of blood cells and the blood forming (hematopoietic) system. Major areas of interest include diseases such as sickle cell anemia, thalassemias, aplastic anemia, iron deficiency anemia, hemolytic anemias, and thrombocytopenia. Other areas of interest include l) morphologic, physiologic, and biochemical aspects of the formation, mobilization, and release of blood cells; 2) erythrocyte metabolism and physiology, globin synthesis, ion transport, and enzymatic pathways; 3) iron metabolism and absorption; 4) erythropoietin and other hematopoietic growth factors; 5) hemoglobin metabolism, structure, function, and genetic control; 6) porphyrins and porphyrias; 7) metabolism and function of white blood cells; and 8) development of genetic therapies.

The Hematology Program has issued several recent initiatives to emphasize research on the biology and genetic regulation of stem cells. Stem cells are crucial to the eventual accomplishment of gene therapy and for improved transplantation of bone marrow cells. An additional area of long-term priority has been the development of improved iron chelating drugs to reduce the toxic iron burden in people who receive multiple blood transfusions for diseases such as Cooley's anemia (thalassemia major).

The Hematology Program is leading a major trans-NIH initiative to make zebrafish genomic resources available to the research community. As a vertebrate, the zebrafish, Danio rerio, is more closely related to humans than are yeast, worms or flies. The zebrafish has a number of valuable features that make it a highly desirable model for the study of vertebrate development. Some genomic resources already exist to facilitate identification of the molecular defects that underlie mutations already known in the zebrafish. The utility of these resources is limited, however, and the mapping infrastructure is insufficiently developed to fully exploit the power of the genetics of this organism. The NIDDK and the National Institute of Child Health and Human Development co-chair the newly established, NIH-wide Zebrafish Coordinating Committee, which manages genomics projects and further develops the utility of the model.

Division-Wide Programs include:

The Centers Program, which consists of: 1) George M. O'Brien Kidney and Urologic Research Centers; 2) Research Centers of Excellence in Pediatric Nephrology and Urology; and 3) Centers of Excellence in Molecular Hematology. The goal of the Centers Program is to reduce adult and pediatric mortality and morbidity from kidney, urologic, and hematologic diseases. The program provides a focus and means for clinical and basic science disciplines to improve the diagnosis, treatment, and prevention of these conditions.

The George M. O'Brien Kidney and Urologic Research Centers conduct interdisciplinary investigations that address basic, clinical, and applied aspects of biomedical research in renal and genitourinary physiology and pathophysiology. Kidney diseases of hypertension and diabetes, renal and urinary tract dysfunction in obstructive diseases of these organs, immune and nonimmune-related mechanisms of glomerular injury and kidney disease, nephrotoxins and cell injury, and benign prostatic hyperplasia are emphasized.

The Research Centers of Excellence in Pediatric Nephrology and Urology currently conduct coordinated, interdisciplinary and multi-institutional studies on mechanisms regulating the development of the kidney and urinary tract and on childhood nephrotic syndrome.

The Centers of Excellence in Molecular Hematology have integrated teams of investigators from a wide range of specialties; share specialized, often expensive equipment and staff; and serve as regional or national resources for other researchers. The Centers provide a focus for multi-disciplinary investigations into gene structure and function; the cellular and molecular mechanisms involved in the generation, maturation and function of blood cells; and the development of strategies for the correction of inherited diseases.

The Clinical Trials Program works in concert with other programs of the Division to develop and manage cooperative clinical trials to prevent or retard major chronic kidney, urologic, and hematologic diseases. The program coordinates and monitors patient recruitment and adherence to interventions for: 1) the Hemodialysis Study; 2) the African American Study of Kidney Disease and Hypertension; 3) the Interstitial Cystitis Clinical Trials Group; 4) the Medical Therapy of Prostatic Symptoms; and 5) the Chronic Prostatitis Collaborative Research Network.

The Developmental Biology and Non-mammalian Systems Program supports fundamental investigation likely to enrich our basic investigative programs. Two broad topic areas, developmental biology and non-mammalian systems, continue to be of substantial relevance to this goal. The Division's basic programs in all three subject areas--Kidney, Urology and Hematology--have experienced increases in grants awarded in developmental biology, a trend we hope to see continued. The Division has identified several barriers to the full exploitation of the rich potential of non-mammalian systems, including their unfamiliarity to study sections and the difficulties of identifying appropriate collaborations. Building bridges between the communities traditionally supported by our programs and experts in other relevant model systems will continue to be one focus of the Division's workshop planning. A workshop on use of Non-Mammalian model systems for study of epithelial transport is planned for December 1999.

The Division has assumed a leadership position in trans-NIH planning for the Zebrafish Program. The zebrafish is a model organism that has emerged as a very valued scientific tool to understand vertebrate development. A major strength of this zebrafish system is the feasibility of mutagenesis screens and positional cloning to identify developmentally important genes. In the coming fiscal year two goals are proposed for this program: 1) establishment of a physical map of the zebrafish genome; and 2) funding of mutagenesis and phenotyping projects to identify additional genetic defects. Funding of these projects will occur through collaborative efforts of the trans-NIH zebrafish coordinating committee, with participation from 18 institutes.

The Genomic Resources for Kidney and Urology Program addresses one of the most promising of the new scientific approaches emerging from the human genome project, namely, the use of systematic methods to assess changes in gene expression in response to injury or disease. A prerequisite for application of these methods to kidney and urology disease is the availability of organ-specific gene profiles. The Division is actively engaged in exploring the best ways to facilitate availability of these methods to our investigative communities.

The Human Immunodeficiency Virus (HIV) Program supports basic and clinical studies on renal and genitourinary tract structure and function, and hematopoietic function in individuals with HIV infection. The program's interests include: 1) the pathogenetic mechanisms of the viral infection on the kidney and genitourinary tract; 2) site(s) of viral replication and/or spread, and the resulting organ dysfunction; and 3) hematologic abnormalities associated with HIV infection and its effects on stem cells and marrow function. Studies on HIV infection focus on: 1) the effect of HIV therapies on marrow function and clinical course of dialysis and transplant patients; 2) the potential interactions of HIV infection and therapies on the immunosuppressive therapy used to prevent transplant rejection; and 3) the effect on organ function. An important new emphasis is research into the development of strategies for gene therapy for HIV, using modification of hematopoietic stem cells. This is based on recent reports of protection against HIV through the use of human fetal stem cells transduced with retroviral vectors expressing a ribozymal gene.

The Manpower Program offers research training and career development awards in the clinical and basic sciences for predoctoral and postdoctoral training and career development. Of particular program interest is training and development of under-represented minority investigators for retention in academic research and the training of more researchers in epidemiology, health services research, pediatric urology and nephrology, pathology, and materials science.

The Minority Health Program supports research on diseases that disproportionately affect minority populations. The program is especially interested in research on the pathogenetic mechanisms, risk factors, and potential treatments for renal disease and hypertension, kidney disease of diabetes, and hemoglobinopathies such as sickle cell disease.

The Small Business Innovation Research (SBIR) Program promotes technological innovation within the American small business community by giving small businesses an increased role in Federal biomedical research. The program works to attract private capital to commercialize the results of federally funded research into basic mechanisms of organ and tissue function and diseases of the kidney, urologic, and hematopoietic systems. The Division's SBIR Program encourages research aimed at understanding the physiology and pathophysiology of diseases of the kidney, urinary tract, and blood and blood-forming systems. The Program promotes the development of: 1) cellular and molecular biology technologies to enhance research in these diseases; 2) bacterial-resistant biomaterials for urinary catheters; 3) noninvasive methods for measuring renal function; 4) tissue engineering; 5) animal models; 6) data and cell banks of large families with polycystic or diabetic kidney diseases; 7) improved methodology for purifying and isolating hematopoietic stem cells; 8) methods to isolate, purify, and characterize cellular receptors for hematopoietic growth factors; 9) development of noninvasive means to measure body iron; 10) generation of cDNA libraries from hematopoietic lineages; and 11) population studies to identify prevalence, incidence, demographics, risk factors, etc., for kidney and urologic diseases.

The Small Business Technology Transfer Research (STTR) Program is authorized under the same law as the SBIR Program. While both programs have similar goals, the STTR Program also encourages and requires collaboration and technology transfer between small businesses and research institutions. The Division's STTR program is interested in supporting research on tissue modeling techniques for renal and urinary tract diseases and basic hematological processes.

The Kidney, Urologic, and Hematologic Diseases Interagency Coordinating Committee was established to coordinate research in kidney, urologic, and hematologic diseases and to aid the efficient exchange of information among NIH institutes and other Federal agencies. The committee meets regularly and prepares an annual report.

The National Kidney and Urologic Diseases Information Clearinghouse was established in 1987 in response to the Health Research Extension Act of 1985. Its goal is to increase knowledge about kidney and urologic diseases among patients, health professionals, and the public. The clearinghouse collects, screens, and disseminates information and educational materials about kidney and urologic diseases. The Clearinghouse also works closely with local and national organizations, as well as professional groups interested in these diseases for the purpose of developing and exchanging educational materials.

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