The inducible stress response was first discovered as a """"""""heat shock"""""""" response in Drosophila, but is now known to be a ubiquitous and highly conserved inducible mechanism to protect cells from various damaging physiological and environmental stresses. In mammals, this pathway is regulated through the activation of heat shock transcription factor 1 (Hsf 1), which induces heat shock proteins (Hsps). This project is based on evidence, both from published studies and from our preliminary data, that the inducible stress response decreases in aging animals. The overall hypothesis of this proposal is that the stress response system of the cochlea is similarly compromised in aged animals, making the sensory cells more vulnerable to stress and hence to cell death, leading to age-related hearing loss (ARHL). Studies in Aim 1 will use CBA mice with normal hearing throughout most of their lifespan to investigate the age-related decrease in the inducible stress response following two stresses: heat and noise.
Aim 2 will investigate the hypothesis that the decrease in the stress response pathway with aging will be reflected in a decrease in the ability to recover from a noise exposure that causes only temporary hearing loss in wild-type mice. Studies in Aim 3 will test the hypothesis that eliminating the stress response in Hsf1 null mice will affect the rate or severity of age-related hearing loss. Studies in Aim 4, which interface with studies in Project 0001, will test the hypothesis that both antioxidant defenses and the inducible stress response contribute to age-related hearing loss. Hsf1 null mice and their wild-type littermates will be maintained on an oxidant-supplemented diet from 8 months to test the effect of antioxidants on ARHL and the stress response.
Aim 5 will generate and characterize two additional transgenic mouse models that express a constitutively active form of HSF1 in the cochlea. These studies of the inducible stress response in the aging cochlea will provide a better understanding of the role of this important protective pathway in ARHL and will provide a rational basis for future interventions to prevent and/or treat presbycusis.
| 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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