The vast majority of hearing and balance impairments are thought to be due to death of sensory hair cells, the receptor cells of the inner ear. These cells are unusually metabolically active and hypersensitive to damage from overstimulation, some therapeutic drugs and environmental toxins, and aging. However, there is enormous variability in structural and functional outcomes of these challenges to the inner ear among both humans and laboratory animals, and a large number of mutations either directly influence the viability of hair cells, or alter susceptibility to ototoxicity. The goals of the research program proposed herein are: A) to better define the cellular and molecular cascades that control hair cell death and survival following exposure to potentially ototoxic agents;B) to use the genetic potential of the zebrafish and the accessibility of the lateral line neuromasts to identify and characterize genes that influence the viability of hair cells when challenged by ototoxic agents;and C) to employ the lateral line system to rapidly screen for small molecules/drugs that protect against damage. Four groups of experiments are proposed: 1) We will molecularly characterize 5 already identified mutations that confer resistance to aminoglycoside antibiotics;2) We will identify distinct pathways resulting in hair cell death using chemical and genetic modifiers of hair cell death;3) We will screen for new genes and drugs that alter the response to aminoglycosides;and 4) We will determine to what degree our findings from the zebrafish lateral line system extend to mammalian systems. In the US, over 31 million adults have trouble hearing. Our research will reveal how the sound-sensing cells of the ear are damaged, identify genes that may underlie the variability in hearing loss, and find drugs that may help in its prevention.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Freeman, Nancy
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University of Washington
Anatomy/Cell Biology
Schools of Medicine
United States
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Stawicki, Tamara M; Hernandez, Liana; Esterberg, Robert et al. (2016) Cilia-Associated Genes Play Differing Roles in Aminoglycoside-Induced Hair Cell Death in Zebrafish. G3 (Bethesda) 6:2225-35
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Thomas, Andrew J; Wu, Patricia; Raible, David W et al. (2015) Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line. Otol Neurotol 36:519-25
Stawicki, Tamara M; Owens, Kelly N; Linbo, Tor et al. (2014) The zebrafish merovingian mutant reveals a role for pH regulation in hair cell toxicity and function. Dis Model Mech 7:847-56
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Esterberg, Robert; Hailey, Dale W; Rubel, Edwin W et al. (2014) ER-mitochondrial calcium flow underlies vulnerability of mechanosensory hair cells to damage. J Neurosci 34:9703-19
Thomas, Andrew J; Hailey, Dale W; Stawicki, Tamara M et al. (2013) Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line. J Neurosci 33:4405-14

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