Systems Biology

Director:  Donna L. Mendrick, Ph.D.

The Division of Systems Biology is focused on using new approaches to solve problems that have a detrimental effect on human health. Studies are conducted to identify important translational biomarkers and pathways of responses that provide predictive, diagnostic, and prognostic value in both the preclinical testing of compounds and the management of patients. An integrated systems biology strategy utilizing genomics, metabolomics, and proteomics technologies is being applied to questions related to the safe and effective use of FDA-approved drugs and devices, and the toxicity of tobacco products. 
 

The following model systems are used to address critical issues including hepatotoxicity, cardiotoxicity, developmental toxicity, disease and toxicity/disease susceptibility:

• pluripotent stem cells
• primary and transformed cell lines
• animal models
• clinical samples
• in silico models
   

New innovative approaches are being developed to:

• identify toxic agents that will cause adverse effects in humans,
• detect and classify pathogenic bacteria and other infectious agents in food and biological products, and improve the diagnostic accuracy of medical imaging 

 

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SYSTEMS BIOLOGY BRANCHES 
 

 

 

Biomarkers and Alternative Models Branch

Mission: 1) To discover and evaluate translational biomarkers of toxicity and disease using cutting edge systems biology approaches in preclinical and clinical studies, and 2) To develop alternative models (e.g., stem cells) to assess toxicity and efficacy of FDA-regulated products. These alternative assays could be higher in throughput and possibly more relevant than conventional assays.

Together, these approaches will improve public health by providing new insights and assays in preclinical safety testing, disease detection, and patient management. 

 

Innovative Safety and Technologies Branch

Mission: To develop innovative approaches for assessing the safety of FDA-regulated products and improving the diagnosis and treatment of disease to improve the lives of Americans. Approaches are broad and encompass studies:

a) identifying new biomarkers
b) developing new innovative methods
c) using proven technologies in new applications to improve public health  

These approaches will help improve the speed and accuracy of the assessments and ensure the safe use of FDA-regulated products. 

 

Personalized Medicine Branch

Mission: To develop biomarkers, technologies, and tools to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Classifications include:

a) genetics
b) sex
c) age
d) epigenetics
e) life-style and environmental factors such as smoking and obesity

Preventions and therapies can then be chosen that maximize benefits while minimizing side effects and unnecessary treatments and tests. Application of personalized medicine has the potential to improve public health and reduce unnecessary costs.

 

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ONGOING SYSTEMS BIOLOGY RESEARCH TOPICS

Liver Toxicity

• Discovering biomarkers of liver toxicity using a systems biology approach to address weaknesses in preclinical assessment of toxicity
• Using cell free microRNA (miRNA) as improved clinical biomarkers of drug-induced liver injury
• Preclinical studies investigating the dose range and proof-of-principle that leflunomide-induced liver injury is enhanced by cytochrome P450 inhibition
• Assessing acetaminophen-induced liver injury and the influence of dietary supplements-potential synergistic interactions
• Identification of new mechanistic human biomarkers of adverse responses to acetaminophen
   

Effects of Potential Endocrine Disruptors

• Evaluation of reproductive and development effects of oxybenzone
   

Stem Cells

• Establishment of mouse embryonic stem cells as an in vitro model to explore developmental toxicity
• An omics approach to investigate the metabolic and endocrine effects of fructose on adipocytes compared to glucose  

Pharmacogenetics and Pharmacogenomics

• Whole genome sequencing to identify genetic susceptibilities to carbamazepine-induced adverse reactions
• Genetic effects on clopidogrel and aspirin adverse events
• Genetic and epigenetic mechanisms of sex differences in the kidney of a rat model system: developing safety biomarkers for FDA-regulated products
• Development of predictive biomarkers for doxorubicin-induced cardiotoxicity using a system biology approach

Food and Biological Product Safety

• Extending the usefulness of a mobile, field-rugged rapid detection technology for select pathogens
• Rapid screening of food or drugs for chemical or microbiological contamination
• Rapid and sensitive detection of Creutzfeldt-Jakob disease agents in tissue and blood donations
   

In silico Approaches to Model Toxicity

• 3D- and 4D-QSDAR modeling applied to various toxicological endpoints
• Understanding and predicting immune-mediated idiosyncratic drug reactions using a molecular modeling approach  
   

Study of Tobacco Toxicity

• In vitro assessments of the toxicity of tobacco smoke in human lung and cardiac cells using a systems biology approach 

 

The NCTR Annual Report contains information on the latest accomplishments and plans for the Division of Systems Biology (formerly the Division of Systems Toxicology) as well as project and publication listings.