Text Size
A A A
Skip Navigation

Home > RePORTER > Project Information

Project InformationProject Information Help

Project Number: 1U01NS074506-01 Contact PI / Project Leader: RUBEL, EDWIN W
Title: DRUG DISCOVERY FOR THE PREVENTION OF HEARING LOSS Awardee Organization: UNIVERSITY OF WASHINGTON
Description
Abstract Text:
DESCRIPTION (provided by applicant): This research program is designed to test the efficacy of candidate drugs, for protection against inner ear receptor cell (hair cell) loss and hearing loss resulting from systemic treatment of patients with gram- negative antibiotics. Loss of inner ear hair cells is the leading cause of hearing loss and balance dysfunction, affecting approximately 31 million Americans. The candidate drugs under investigation will be analogs of PR0T01, a small molecule, drug-like compound discovered using a well-characterized chemical screen of lateral line mechanosensory hair cells of larval zebrafish, in vivo. PR0T01 exposure provides robust protection of zebrafish hair cells hair cells against a broad range of aminoglycoside antibiotic conditions and exposure levels, and protects rodent inner ear hair cells in vitro and in vivo. The following Specific aims are proposed. 1) Screen analogs of PR0T01 for those "hits" with optimized protection of hair cells and other drug characteristics using a well characterized, robust and sensitive zebrafish lateral line hair cell assay. 2) Evaluate the most promising new PROTO analogs with secondary assays to determine lead compounds from among promising hits, based on detailed assessment of neomycin-induced hair cell loss, acute and chronic gentamicin-induced hair cell loss, normal efficacy of aminoglycoside as a bacteriostatic agent via MIC/MBL tests, and uptake of the aminoglycoside by hair cells. These experiments will continue to utilize the larval zebrafish hair cell platform. 3) Evaluate lead PROTO analogs for their ability to confer hearing protection against aminoglycoside-induced damage in vivo in mature rats by testing with a well-established auditory brain stem response (AER) assay and by quantitative assessment of inner ear hair cell integrity, 4) Direct IND and phase I clinical preparation of lead compounds in conjunction with NIH supported contractors. The studies outlined in the specific aims will provide a focused analysis of the ability of PR0T01 analogs to protect hair cells from drug-induced damage. Optimization of lead compounds and validation in a mammalian system will provide essential drug development information for future clinical trials in human patients. PUBLIC HEALTH RELEVANCE: Hearing and balance disorders, due to injury or loss of the inner ear cells affects over 30 million Americans and almost a billion people in the world. One of the leading causes is treatment with medicinal drugs used for infectious diseases or cancer treatments. The goal of the research proposed here is to develop drugs that prevent the hearing loss, while preserving the medicinal benefits.
Public Health Relevance Statement:
Hearing and balance disorders, due to injury or loss of the inner ear cells affects over 30 million Americans and almost a billion people in the world. One of the leading causes is treatment with medicinal drugs used for infectious diseases or cancer treatments. The goal of the research proposed here is to develop drugs that prevent the hearing loss, while preserving the medicinal benefits.
NIH Spending Category:
Mental Health; Neurosciences; Prevention
Project Terms:
Acute; Affect; Age Factors; Aging; American; Aminoglycoside Antibiotics; Aminoglycosides; analog; Animals; Anti-Bacterial Agents; Antibiotics; Auditory; base; Biological Assay; cancer therapy; cell injury; Cells; Characteristics; Chemicals; Chronic; Cisplatin; Clinical; Clinical Trials; Communicable Diseases; Consultations; Contractor; design; Development; drug candidate; drug development; drug discovery; Drug Kinetics; Drug usage; Ear structure; efficacy testing; Environmental Risk Factor; Epithelium; equilibration disorder; Equilibrium; Essential Drugs; Evoked Potentials, Auditory, Brain Stem; Functional disorder; Future; Gentamicins; Goals; Habilitation; Hair Cells; Health; Hearing; hearing impairment; Hearing problem; Hearing Tests; Histocytochemistry; Human; In Vitro; in vivo; Injury; Investigation; Investigational Drugs; Labyrinth; lateral line; Lead; Measures; Neomycin; neoplastic; Patients; Performance; Pharmaceutical Preparations; Phase; Platinum; pre-clinical; Preparation; prevent; Prevention; Principal Investigator; programs; Property; Publishing; Rattus; Receptor Cell; Research; research clinical testing; research study; Rodent; Screening procedure; Sensory; small molecule; small molecule libraries; System; Testing; Therapeutic; Therapeutic Agents; United States National Institutes of Health; uptake; Validation; Zebrafish



The RePORTER database is available to all public users at http://exporter.nih.gov/. As the data are available for bulk download, the RePORTER system reserves the right to block IP addresses that fail to adhere to instructions in the system’s robots.txt files or submit requests at a rate that negatively impacts service delivery to other users. RePORTER reserves the right to terminate any automated query to the RePORTER application that negatively affects service delivery to other users.

Page Last Updated on March 18, 2013
This site is best viewed with Internet Explorer (7.0 or higher) or Mozilla Firefox (3.0).

NIH...Turning Discovery Into Health®
RePORTER2