Mechanisms of Sensory Hair Cell Survival and Death

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Our basic science studies are focused on the signal transduction and intercellular communication pathways that are activated in response to hair cell stress. We previously examined the roles of heat shock proteins (HSPs) in promoting survival of hair cells under stress. We showed that HSP induction is a critical stress response in the inner ear that can protect hair cells against major stresses, including exposure to both classes of ototoxic drugs (i.e., the aminoglycoside antibiotics and cisplatin). We showed that pro-survival induction of HSP expression is relatively low in hair cells and is more robust in supporting cells and resident macrophages. These data indicate that hair cells may have a reduced capacity to induce autonomous pro-survival signaling in response to stress, and that non-autonomous signals from supporting cells and macrophages function as critical mediators of pro-survival signaling when hair cells are under stress. We showed previously that glia-like supporting cells secrete HSP70 in a stress-induced response that protects hair cells against death caused by exposure to ototoxic drugs. This year we have demonstrated that secretory exosomes act as mediators of the non-autonomous cellular signaling that occurs between supporting cells and hair cells. Exosomes are a class of extracellular vesicles that carry protein and nucleic acid cargo and can influence function of recipient cells. Our data indicate that exosome release is required for the protective effect of heat shock, and isolated exosomes reduce ototoxic drug-induced hair cell death. We have shown that HSP70 interacts with TLR4 on hair cells to mediate this protection. These data were published in Journal of Clinical Investigation. Our translational studies consist of preclinical experiments aimed at developing therapies to preserve hearing in humans exposed to ototoxic drugs or other hair cell stresses. Toward this goal we are currently examining whether exosomes can be engineered as therapeutic delivery vehicles for clinical treatment of hearing loss. In a second translational study we have examined the pharmacokinetics of platinum-based chemotherapy drugs to determine the relationship between platinum uptake in the inner ear and cisplatin ototoxicity. Our preliminary data suggest that cisplatin readily enters the cochlea and remains there indefinitely, while carboplatin is largely excluded from the cochlea and does not cause hearing loss. Oxaliplatin treatment results in some cochlear uptake of platinum but no hearing loss. These data were published in Journal of the Association for Research in Otolaryngology. Clinical studies: We are examining the extent to which statins reduce cisplatin-induced hearing loss in humans. We recently completed a retrospective study in collaboration with University of Rochester Otolaryngology Department and Walter Reed National Military Medical Center to examine this question. We also completed our prospective study in which we tested the hearing of head and neck cancer patients before onset of cisplatin therapy and after cessation of cisplatin therapy to determine if statins reduce cisplatin ototoxicity in this patient population. Our analyses of the combined prospective and retrospective studies indicate that subjects undergoing cisplatin therapy to treat head and neck cancer who are concurrently taking atorvastatin experience reduced incidence and severity of cisplatin-induced hearing loss compared to subjects not taking a statin. These data are described in a manuscript that has received favorable reviews at Journal of Clinical Investigation. Based on these data, we have initiated development of a phase 3, randomized, placebo-controlled study to determine the extent to which atorvastatin reduces cisplatin-induced hearing loss in this population. The human subjects protocol for this study has completed NIDCD scientific review and is currently awaiting review by the NIH Central IRB.