. The genetic basis of age-related hearing loss (presbycusis) is poorly understood because of the extreme difficulty in studying such a late-onset genetically complex disorder. The laboratory mouse provides promising models for studying human presbycusis because age-related hearing loss (AHL) is common in inbred mouse strains and mice are more amenable to genetic analyses. We have shown that a gene on Chromosome 10 (ahl) is a major susceptibility factor for AHL in more than 10 inbred strains of mice and that three other genes (ah!2, ah!4, and a/7/8) and a mitochondrial mutation also contribute to hearing loss in particular inbred strains. We hypothesize that the genetic predisposition and the pathophysiological pathways involved in the mouse are also involved in humans and that further genetic and pathological studies of AHL in mice will add significantly to our understanding of presbycusis in humans.
Our specific aims are to (1) formally test the hypothesis that a Cdh23 variant is responsible for the hearing loss attributed to the ahl locus by gene """"""""knock-in"""""""" experiments and analyze the molecular mechanisms and interactions with other genes that underlie its effect on AHL;(2) refine the genetic map positions and attempt to identify the genes responsible for a/7/2, ah!4, and a/7/8;and (3) characterize the inner ear pathologies associated with the AHL loci and inbred mouse strains developed in Aims 1 and 2. The long-term objectives of this research are to identify the major genetic factors and molecular mechanisms that influence predisposition, time of onset, and pathological presentation of AHL in inbred strains of mice as models for human presbycusis. Relevance to public health. Presbycusis is the most common sensory deficit in human populations; about 1 in 3 adults older than 60 suffer from a significant hearing loss. The proposed genetic and pathological studies of age-related hearing loss in mice will provide important insights to improve our understanding of the major genetic factors and molecular pathways that influence human presbycusis, which could contribute to the development of diagnostics, preventive interventions, and therapies.

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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Watson, Bracie
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Jackson Laboratory
Bar Harbor
United States
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Johnson, Kenneth R; Tian, Cong; Gagnon, Leona H et al. (2017) Effects of Cdh23 single nucleotide substitutions on age-related hearing loss in C57BL/6 and 129S1/Sv mice and comparisons with congenic strains. Sci Rep 7:44450
Ding, Dalian; Jiang, Haiyan; Chen, Guang-Di et al. (2016) N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in ?-glutamyl transferase 1 deficient mice. Aging (Albany NY) 8:730-50
Johnson, Kenneth R; Longo-Guess, Chantal M; Gagnon, Leona H (2015) A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice. Mamm Genome 26:338-47
Perrin, Benjamin J; Strandjord, Dana M; Narayanan, Praveena et al. (2013) ýý-Actin and fascin-2 cooperate to maintain stereocilia length. J Neurosci 33:8114-21
Johnson, Kenneth R; Gagnon, Leona H; Longo-Guess, Chantal et al. (2012) Association of a citrate synthase missense mutation with age-related hearing loss in A/J mice. Neurobiol Aging 33:1720-9
Kane, Kelly L; Longo-Guess, Chantal M; Gagnon, Leona H et al. (2012) Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice. Hear Res 283:80-8
Johnson, Kenneth R; Yu, Heping; Ding, Dalian et al. (2010) Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice. Hear Res 268:85-92
Shin, Jung-Bum; Longo-Guess, Chantal M; Gagnon, Leona H et al. (2010) The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair-cell stereocilia, underlies early-onset hearing loss of DBA/2J mice. J Neurosci 30:9683-94
Zheng, Qing Yin; Ding, Dalian; Yu, Heping et al. (2009) A locus on distal chromosome 10 (ahl4) affecting age-related hearing loss in A/J mice. Neurobiol Aging 30:1693-705
Noben-Trauth, Konrad; Johnson, Kenneth R (2009) Inheritance patterns of progressive hearing loss in laboratory strains of mice. Brain Res 1277:42-51

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