STRESS PATHWAYS IN THE AGING COCHLEA

诱导应激反应最初是在果蝇身上发现的一种“热休克”反应，

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.