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, exposure to some therapeutic drugs and environmental toxins, and to aging. However, there is enormous variability in structural and functional outcomes of these challenges to the inner ear among both humans and laboratory animals. The goals of our research program are to facilitate development of therapeutic agents to prevent hearing loss through understanding the cellular pathways and molecular identities of potential therapeutic targets that regulate death and survival of inner ear hair cells. During the proposed grant period we will: i) use the genetic potential and the accessibility of zebrafish lateral line neuromasts to better define cellular and molecular cascades that control hair cell death and survival following exposure to potentially ototoxic agents;ii) characterize drugs and small molecules that influence the susceptibility of hair cells when challenged by ototoxic agents;and iii) determine the efficacy of newly discovered genes and drugs in mammal inner ear and initiate preclinical development. Three groups of experiments are proposed: a) further examine intracellular calcium trafficking and ototoxin trafficking as determinants in the fate of ototoxin-exposed zebrafish and mammalian hair cells;b) determine intracellular pathways and mammalian efficacy of mutations in the Cc2d2a gene for hair cell protection in zebrafish and mammals;and c) further development of drugs and small molecule "hits" from completed screens toward preclinical efficacy for hearing protection.

Public Health Relevance

In the US, over 36 million adults have trouble hearing. There are a variety of causes but no clinically proven treatments to restore normal hearing or prevent hearing loss. Our research will reveal how the sound sensing cells of the ear are damaged, identify pathways that may underlie the variation in susceptibility to hearing loss, and discover drugs that may prevent hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC005987-11
Application #
8583259
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2003-04-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$572,208
Indirect Cost
$201,847
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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
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
Coffin, Allison B; Williamson, Kay L; Mamiya, Anna et al. (2013) Profiling drug-induced cell death pathways in the zebrafish lateral line. Apoptosis 18:393-408
Bhandiwad, Ashwin A; Zeddies, David G; Raible, David W et al. (2013) Auditory sensitivity of larval zebrafish (Danio rerio) measured using a behavioral prepulse inhibition assay. J Exp Biol 216:3504-13
Esterberg, Robert; Hailey, Dale W; Coffin, Allison B et al. (2013) Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death. J Neurosci 33:7513-25
Ou, Henry C; Lin, Vincent; Rubel, Edwin W (2013) "In-bone" utricle cultures--a simplified, atraumatic technique for in situ cultures of the adult mouse (Mus musculus) utricle. Otol Neurotol 34:353-9
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
Coffin, Allison B; Rubel, Edwin W; Raible, David W (2013) Bax, Bcl2, and p53 differentially regulate neomycin- and gentamicin-induced hair cell death in the zebrafish lateral line. J Assoc Res Otolaryngol 14:645-59
Esterberg, Robert; Coffin, Allison B; Ou, Henry et al. (2013) Fish in a Dish: Drug Discovery for Hearing Habilitation. Drug Discov Today Dis Models 10:

Showing the most recent 10 out of 25 publications