Millions of people in the U.S. suffer from hearing loss caused by permanent damage to sensory hair cells of the inner ear. Hair cell damage often results from exposure to excessive sound or particular licit drugs, such as the aminoglycoside antibiotics. The overall goal of this proposed research is to discover novel drugs that prevent aminoglycoside-induced hair cell death and preserve hearing loss in patients requiring these life-saving antibiotics. For this work we will use the zebrafish lateral line, which is a powerful n vivo model for studying mechanisms of hair cell death and protection. Our preliminary data indicate that caffeine significantly protects hair cells from aminoglycoside damage. The specific goal of this research is to determine the mechanism by which caffeine confers protection, and to identify additional natural products that prevent aminoglycoside-induced hair cell death. This project has two specific aims: 1) Test the hypothesis that caffeine otoprotection is mediated by inhibition of p53 and adenosine signaling, and 2) Test the hypothesis that natural products are novel agents for preventing aminoglycoside ototoxicity. Our previous research demonstrates that aminoglycosides activate p53 in damaged hair cells. Caffeine is a known p53 inhibitor, in part via its interaction with adenosine signaling.
For Aim 1, we will use pharmacologic and genetic manipulation to modulate p53 and adenosine receptors during aminoglycoside treatment. Caffeine is a plant alkaloid and other natural products, including plant and microbial extracts, likely represent an untapped source of novel otoprotective agents.
In Aim 2, we will conduct a series of drug discovery experiments to identify natural products that act as hair cell protectants and to characterize their mechanisms of action. These studies will provide new lead compounds for auditory drug development. By specifically targeting caffeine, a widely used compound with a well-characterized safety profile, we increase the likelihood that our findings may be quickly translated into clinical application. Student researchers are integral to all aspect of this project. Students will learn cutting- edge cell biology and drug discovery techniques that will bolster their biomedical career opportunities, while actively contributing to the discovery of new compounds that prevent drug-induced hearing loss.

Public Health Relevance

Loss of sensory cells in the inner ear is the cause of most cases of human deafness. This research aims to identify novel natural products that may prevent sensory cell loss due to certain types of toxins so that we may preserve hearing. We use zebrafish as a model system for this research because we can test hundreds of compounds quickly and efficiently, cutting down on the time to develop new drugs to prevent hearing loss.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZAT1-HS (14))
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Freeman, Nancy
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Washington State University
Schools of Arts and Sciences
United States
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Neveux, Sarah; Smith, Nicole K; Roche, Anna et al. (2017) Natural Compounds as Occult Ototoxins? Ginkgo biloba Flavonoids Moderately Damage Lateral Line Hair Cells. J Assoc Res Otolaryngol 18:275-289
Kruger, Matthew; Boney, Robert; Ordoobadi, Alexander J et al. (2016) Natural Bizbenzoquinoline Derivatives Protect Zebrafish Lateral Line Sensory Hair Cells from Aminoglycoside Toxicity. Front Cell Neurosci 10:83
Coffin, Allison B; Ramcharitar, John (2016) Chemical Ototoxicity of the Fish Inner Ear and Lateral Line. Adv Exp Med Biol 877:419-37