Presbycusis or age-related hearing loss (AHL) is the most common sensory deficit in aging human populations and a major factor in reducing the quality of life of the elderly. Genetic studies in humans are difficult because of the late onset of the condition and because non-genetic factors such as noise trauma, disease, and ototoxic drugs confound interpretations. The laboratory mouse provides promising models for human presbycusis because AHL is common in inbred mouse strains and mice are more amenable to detailed genetic and pathological analyses. Mice and humans often share the same genes and inner ear pathologies underlying monogenic hearing disorders, so genetic studies of AHL in mice are likely to add significantly to our understanding of human presbycusis.
Aim 1 of this proposal is to complete the analysis of genetically engineered knock-in mice to verify that a splice variant of the cadherin 23 gene (Cdh23) underlies ahl, a variant conferring AHL susceptibility to multiple inbred strains, and to genetically analyze strain-specific influences on its manifestation. Cdh23 encodes a component of the stereocilia tip link, which is essential to hair cell mechanotransduction, but it is unclear how the Cdh23ahl variant influences AHL. We previously showed that a missense mutation of fascin 2 (FSCN2), an actin bundling protein of hair cell stereocilia, underlies ahl8, a locus on distal Chr 11 that contributes to the early onset hearing loss of DBA/2J mice.
Aim 2 of this proposal is to further elucidate the role of FSCN2 in auditory function by examining hair bundle morphology and hearing loss progression in Fscn2 knockout mice, and by genetically mapping strain-specific loci that modify the effect of Fscn2ahl8 on hearing loss. The chromosomal location and strain distribution of a citrate synthase (Cs) missense mutation strongly supports it as a candidate for the ahl4-related hearing loss of A/J mice.
Aim 3 is to determine the causative nature of this mutation on AHL by a BAC rescue approach, in which a wild-type Cs transgene is integrated into the genome of A/J mice. Another aspect of this aim is to investigate the effects of the A/J ahl4 (Cs) variant and a previously described mt-Tr variant on mitochondrial function and oxidative stress in cochlear tissues. We recently discovered that mice with a null mutation of gamma-glutamyltransferase 1(Ggt1), which are glutathione deficient, exhibit a progressive hearing loss that is associated with a selective loss of cochlear inner hair cells.
Aim 4 is to examine in detail the progression of inner ear pathologies and to measure glutathione-related oxidative stress parameters related to the hearing loss of Ggt1 mutant mice.
Aim 5 of this proposal is to refine the chromosomal locations and test candidate genes for three newly mapped loci that contribute to AHL in A/J mice (ahl9 on Chr 11) and NOD/ShiLtJ mice (ahl10 on Chr 1 and ahl11 on Chr 6).

Public Health Relevance

Presbycusis or age-related hearing loss (AHL) is the most common sensory deficit in aging human populations and a major factor in reducing the quality of life of the elderly. Genetic studies in humans are difficult because of the late onset of the condition and because non-genetic factors such as noise trauma, disease, and ototoxic drugs confound interpretations. AHL is common in inbred mouse strains, and mice are more amenable to detailed genetic and pathological analyses, which could add significantly to our understanding of presbycusis in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005827-10
Application #
8399008
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Watson, Bracie
Project Start
2003-05-05
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
10
Fiscal Year
2013
Total Cost
$417,484
Indirect Cost
$160,275
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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
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
Johnson, Kenneth R; Longo-Guess, Chantal; Gagnon, Leona H et al. (2008) A locus on distal chromosome 11 (ahl8) and its interaction with Cdh23 ahl underlie the early onset, age-related hearing loss of DBA/2J mice. Genomics 92:219-25
Le, Tima; Keithley, Elizabeth M (2007) Effects of antioxidants on the aging inner ear. Hear Res 226:194-202
Johnson, Kenneth R; Zheng, Qing Yin; Noben-Trauth, Konrad (2006) Strain background effects and genetic modifiers of hearing in mice. Brain Res 1091:79-88
Keithley, Elizabeth M; Canto, Cecilia; Zheng, Qing Yin et al. (2005) Cu/Zn superoxide dismutase and age-related hearing loss. Hear Res 209:76-85

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