This project focuses on analysis of the genetic controls and physiological regulators that modulate hearing loss in a population of genetically heterogeneous mice. The test population will consist of 600 animals bred as the progeny of (CAST/Ei X 129S1/SvImJ)F1 females and (C3H/HeJ X FVB/NJ)F1 males. Each mouse generated in this four-way cross is genetically unique, and a full sib to each other animal in the population. Each mouse will be tested for hearing acuity by auditory brainstem response at ages 2, 8, 14, 18 and 22 months. Half of the 600 mice will be exposed to noise-induced cochlear injury at age 14.5 months. SNP-based genotyping at each of 300 loci will provide a genomic map of loci modulating hearing acuity, its change over age, and its resistance to noise-induced damage (Aim 1).
Aim 2 will test the hypothesis that hearing loss is related to, and predictable by, individual differences in cellular resistance to oxidative cytotoxic stress, using in vitro analyses of fibroblast cell lines from each tested mouse. This strategy reflects recent evidence that mutations that retard aging and extend life span in mice may do so by alterations of stress-sensitivity in multiple cell types, including fibroblasts.
Aim 3 will test the hypothesis that the genes, and potentially the non-genetic factors, that modulate functional hearing loss and cellular stress resistance also affect cochlear hair cell loss and oxidative damage to cochlear structures.
Aim 4 tests a series of related hypothesis concerning the effects of early-life growth, maturation, and hormone patterns on mid- and late-life stress resistance and functional outcome, including hearing loss.
Aim 5 will measure a range of age-sensitive traits, including indices of immunity and visual function, to test the hypothesis that inter-individual differences in age-related hearing loss are linked to differences among mice in multiple aspects of aging. This strategy will also yield, as a useful byproduct, a great deal of genetic information about loci that modulate growth, maturation, stress resistance, cataracts, hormones, and immunity in young and older mice. The approach chosen will permit a comprehensive assessment of the extent to which age-depending alterations in hearing are molded by genetic, cellular and hormonal factors that time the aging process in mice.
| Altschuler, R A; Dolan, D F; Halsey, K et al. (2015) Age-related changes in auditory nerve-inner hair cell connections, hair cell numbers, auditory brain stem response and gap detection in UM-HET4 mice. Neuroscience 292:22-33 |
| Schacht, Jochen; Altschuler, Richard; Burke, David T et al. (2012) Alleles that modulate late life hearing in genetically heterogeneous mice. Neurobiol Aging 33:1842.e15-29 |
| Gong, Tzy-Wen; Fairfield, Damon A; Fullarton, Lynne et al. (2012) Induction of heat shock proteins by hyperthermia and noise overstimulation in hsf1 -/- mice. J Assoc Res Otolaryngol 13:29-37 |
| Sha, Su-Hua; Kanicki, Ariane; Halsey, Karin et al. (2012) Antioxidant-enriched diet does not delay the progression of age-related hearing loss. Neurobiol Aging 33:1010.e15-6 |
| Miller, Richard A; Dolan, David; Han, Melissa et al. (2011) Resistance of skin fibroblasts to peroxide and UV damage predicts hearing loss in aging mice. Aging Cell 10:362-3 |
| Leiser, Scott F; Miller, Richard A (2010) Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice. Mol Cell Biol 30:871-84 |
| Sha, Su-Hua; Chen, Fu-Quan; Schacht, Jochen (2010) PTEN attenuates PIP3/Akt signaling in the cochlea of the aging CBA/J mouse. Hear Res 264:86-92 |
| Sha, Su-Hua; Chen, Fu-Quan; Schacht, Jochen (2009) Activation of cell death pathways in the inner ear of the aging CBA/J mouse. Hear Res 254:92-9 |
| Sha, Su-Hua; Kanicki, Ariane; Dootz, Gary et al. (2008) Age-related auditory pathology in the CBA/J mouse. Hear Res 243:87-94 |
| Jiang, Hongyan; Talaska, Andra E; Schacht, Jochen et al. (2007) Oxidative imbalance in the aging inner ear. Neurobiol Aging 28:1605-12 |
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