Mechanisms of Sensory Hair Cell Death and Survival

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DESCRIPTION (provided by applicant): Sensory hair cells are hypersensitive to death induced by noise, aging, and some therapeutic drugs. Two major classes of ototoxic drugs are the aminoglycoside antibiotics and the antineoplastic agent cisplatin. We plan to take advantage of a unique in vitro preparation of the adult mouse utricle that allows us to examine the rrechanisms underlying ototoxic hair cell death and survival at the molecular level. Understanding these cellular mechanisms will be critical for the design of therapies aimed at preventing or reversing hearing loss. The induction of heat shock proteins (HSPs) in response to cellular stress is a ubiquitous and highlyconserved response that can significantly inhibit apoptosis in some systems. Induction of HSPs occurs in hair cells in response to a variety of stimuli. However, there are no studies on the effects of HSPs on ototoxic drug-induced hair cell death. More importantly, there are no data available regarding the cellular interactions between HSPs and apoptotic proteins in hair cells in response to any stimulus. Our preliminary data demonstrate that in vitro heat shock treatment inhibits hair cell death in response to both neomycin and cisplatin exposure. The experiments in this proposal are designed to test the hypothesis that the protective effect of heat shock against ototoxic drug-induced hair cell death is the result of HSP-mediated inhibition of specific apoptotic signaling pathways. Four groups of experiments are proposed: 1). To examine the similarities and differences between the molecular mechanisms mediating cisplatin- vs. aminoglycoside-induced hair cell death. 2). To determine whether heat shock treatment is sufficient to induce a shift in the dose-response relationship between ototcxic drug concentration and hair cell survival. 3). To determine whether induction of HSP-70 is necessary and sufficient for the protective effect of heat shock against ototoxic hair cell apoptosis. 4). To investigate the interactions between HSPs and apoptotic proteins in hair cells exposed to ototoxic drugs.