Molecular studies of hair cell death

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DESCRIPTION (provided by applicant): Sensory hair cell death is responsible for the vast majority of human hearing loss and balance disorders. Aging, exposure to noise and therapeutic drugs such as aminoglycosides are all known direct causes of hair cell death. Recent studies have shown cisplatin-and neomycin-induced hair cell death to be caspase-dependent in the mammalian inner ear in vitro. In many cell types across a variety of species, an orderly activation of caspases, a family of cysteine proteases, is a hallmark of cell death. These molecules are segregated into upstream initiators and downstream effectors, where the latter are cleaved and activated by the former. When activated, caspases degrade the cytoskeletal and nuclear scaffolds as well as survival promoting molecules. Although 14 mammalian caspases have been identified to date, the role of specific caspases in mediating hair cell death is unclear. This research project seeks to thoroughly characterize the activation and inhibition of specific caspases in gentamicin-induced auditory hair cell death using an avian in vitro system. The first set of experiments is designed to detect the activated forms of specific caspases in hair cells damaged by aminoglycosides. The next set of experiments investigates whether inhibition of upstream caspases prevents activation of the downstream members. The last set of experiments focuses on evaluating the effects of caspase inhibitors on hair cell survival after gentamicin exposure. Knowledge gained from these studies will provide new insights on key mediators in hair cell death and contribute to the development of better otoprotective therapies.