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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005987-09
Application #
8113145
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2003-04-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$515,851
Indirect Cost
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chowdhury, Sarwat; Owens, Kelly N; Herr, R Jason et al. (2017) Phenotypic Optimization of Urea-Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss. J Med Chem :
Hailey, Dale W; Esterberg, Robert; Linbo, Tor H et al. (2017) Fluorescent aminoglycosides reveal intracellular trafficking routes in mechanosensory hair cells. J Clin Invest 127:472-486
Sebe, Joy Y; Cho, Soyoun; Sheets, Lavinia et al. (2017) Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse. J Neurosci 37:6162-6175
Esterberg, Robert; Linbo, Tor; Pickett, Sarah B et al. (2016) Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death. J Clin Invest 126:3556-66
Yoshimatsu, Takeshi; D'Orazi, Florence D; Gamlin, Clare R et al. (2016) Presynaptic partner selection during retinal circuit reassembly varies with timing of neuronal regeneration in vivo. Nat Commun 7:10590
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
Suli, Arminda; Pujol, Remy; Cunningham, Dale E et al. (2016) Innervation regulates synaptic ribbons in lateral line mechanosensory hair cells. J Cell Sci 129:2250-60
Thomas, Eric D; Cruz, Ivan A; Hailey, Dale W et al. (2015) There and back again: development and regeneration of the zebrafish lateral line system. Wiley Interdiscip Rev Dev Biol 4:1-16
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
Suli, Arminda; Guler, Ali D; Raible, David W et al. (2014) A targeted gene expression system using the tryptophan repressor in zebrafish shows no silencing in subsequent generations. Development 141:1167-74

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