In the United States, roughly 10% of the total population is exposed to hazardous levels of noise in the workplace on a daily basis (National Institute for Occupational Safety and Health, //www.cdc.gov/NIOSH/). The damage sustained by the cochlea from chronic impulse noise (subsonic) or sudden blast exposure (supersonic) leads to permanent and debilitating hearing loss and tinnitus. Pre-exposure diagnostics and the development of targeted therapies are sorely needed. Estimates from human twin studies suggest heritability for noise induced hearing loss (NIHL) of approximately 36% and although several candidate gene association studies for NIHL have been conducted, however;each lacks power due to the difficulties in finding well-characterized cohorts of sufficient size. The similarities, both anatomically and genetically, between the mouse and human inner ears, coupled with the known strain variation in phenotypes, makes the mouse an ideal model for gene discovery. In this application we propose two specific aims to identify genes and pathways that confer susceptibility to NIHL. Our overriding hypothesis is that among inbred strains of mice there are genetic variants relevant to the molecular mechanisms and pathways underlying susceptibility to NIHL. The primary aim of this study is to comprehensively define loci that contribute to this variation using Genome-Tagged Mice (Aims 1a), to perform high-resolution mapping of the same and additional loci using a Hybrid Mouse Diversity Panel (Aim 1b) and to integrate this with cochlear transcript levels to model biologic networks and identify causal variants (Aims 1c and 2). The findings from the experiments described in this application will form the basis for hypotheses to be tested in human populations.

Public Health Relevance

There is evidence in both mice and humans that there is a heritable component to noise-induced hearing loss (NIHL). The similarities, both anatomically and genetically, between the mouse and human inner ears, coupled with the known strain variation in phenotypes, makes the mouse an ideal model the genetic analysis of strain variation using high-resolution mapping strategies. The primary aim of this study is to comprehensively define loci that contribute to this variation using novel and straight-forward methodologies. The findings from the experiments described in this application will form the basis for hypotheses to be tested in human populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
7R01DC010856-04
Application #
8725407
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2013-08-30
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$442,581
Indirect Cost
$162,145
Name
University of Southern California
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Kari, Elina; Schrauwen, Isabelle; Llaci, Lorida et al. (2017) Compound heterozygous mutations in MASP1 in a deaf child with absent cochlear nerves. Neurol Genet 3:e153
Myint, Anthony; White, Cory H; Ohmen, Jeffrey D et al. (2016) Large-scale phenotyping of noise-induced hearing loss in 100 strains of mice. Hear Res 332:113-120
Salehi, Pezhman; Myint, Anthony; Kim, Young J et al. (2016) Genome-Wide Association Analysis Identifies Dcc as an Essential Factor in the Innervation of the Peripheral Vestibular System in Inbred Mice. J Assoc Res Otolaryngol 17:417-31
Lavinsky, Joel; Ge, Marshall; Crow, Amanda L et al. (2016) The Genetic Architecture of Noise-Induced Hearing Loss: Evidence for a Gene-by-Environment Interaction. G3 (Bethesda) 6:3219-3228
Lavinsky, Joel; Crow, Amanda L; Pan, Calvin et al. (2015) Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss. PLoS Genet 11:e1005094
Crow, Amanda L; Ohmen, Jeffrey; Wang, Juemei et al. (2015) The Genetic Architecture of Hearing Impairment in Mice: Evidence for Frequency-Specific Genetic Determinants. G3 (Bethesda) 5:2329-39
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Ohmen, Jeffrey; Kang, Eun Yong; Li, Xin et al. (2014) Genome-wide association study for age-related hearing loss (AHL) in the mouse: a meta-analysis. J Assoc Res Otolaryngol 15:335-52
Ho, Maria K; Li, Xin; Wang, Juemei et al. (2014) FVB/NJ mice demonstrate a youthful sensitivity to noise-induced hearing loss and provide a useful genetic model for the study of neural hearing loss. Audiol Neurotol Extra 4:1-11

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