Mechanisms of Sensory Hair Cell Survival and Death

National Institute On Deafness And Other Communication Disorders

Investigators

Linked publications, trials & patents

Abstract

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 major 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 cochlear 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. This year we have begun to examine the roles of cochlear resident macrophages as regulators of the inner ear responses to stress. We have conducted a single-nucleus RNA-sequencing (snRNA-Seq) study to examine the cellular diversity of cochlear macrophages as well as their responses to systemic treatment with the ototoxic anti-cancer drug cisplatin. Our data reveal novel insights into the macrophage cell types that exist in the inner ear and they illuminate the roles these macrophages play in the cochlear response to cisplatin-induced damage. A manuscript describing these data is currently in preparation. 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. We previously showed that the FDA-approved cholesterol-lowering drug lovastatin reduces cisplatin-induced hearing loss in mice, and we have now replicated that finding using another drug in the same class, atorvastatin. These data indicate that statins are a class of drugs that hold potential to protect the hearing of patients undergoing lifesaving anti-cancer treatment with cisplatin. Our clinical studies are currently focused on determining the extent to which statins reduce cisplatin-induced hearing loss in humans. We previously showed 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 (Fernandez et al 2021 PMCID: PMC7773379). 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. This project was awarded a 2020 NIH Bench to Bedside Award. The human subjects protocol for this study has been approved by the NIH Central IRB. This year we submitted an application for an NIH U01 Cooperative Agreement to support this multi-site study. In addition are currently working with several universities and government agencies to develop a large database of patient audiograms that will allow us to more deeply examine the relationship between statin use and cisplatin-induced hearing loss.