Mechanisms of Sensory Hair Cell Survival and Death

National Institute On Deafness And Other Communication Disorders

Investigators

Linked publications & trials

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. 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 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. The mechanisms underlying the protective effect of atorvastatin are unclear; however, the hallmark activity of statins is inhibition of HMG Co-A reductase, resulting in reduced serum cholesterol. Thus, to begin to address the mechanisms underlying statin-induced protection, we asked whether a genetic model with reduced serum cholesterol is also protective. We used mice carrying a null mutation of Pcsk9, encoding a protein that plays a pivotal role in lipid metabolism. Pcsk9 knockout (Pcsk9 KO) mice have reduced serum cholesterol, and we find that Pcsk9 KO mice are resistant to cisplatin-induced hearing loss. These data indicate that systemic cholesterol reduction increases resistance to cisplatin-induced hearing loss, and they suggest that the observed protective effect of atorvastatin against cisplatin-induced damage is mediated by cholesterol modulation. A manuscript describing these data is currently in internal review prior to submission for publication. 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 a randomized, placebo-controlled study to determine the extent to which atorvastatin reduces cisplatin-induced hearing loss in this population. This study is now open and enrolling participants (Clinical trials.gov NCT04915183). In addition, we have collaborated with several universities and partner government agencies to develop the Enhancing Cancer Hearing Outcomes (ECHO) data resource that now contains over 6,000 audiograms from over 1200 patients treated with cisplatin at eight collaborating sites. This resource will allow us and others to examine additional questions about the relationships between medications and hearing loss. We have recently used our ECHO resource to examine cisplatin dosing regimens in patients with head and neck cancer and showed that compared to traditional high-dose cisplatin treatment every three weeks, weekly low-dose cisplatin significantly reduces the incidence and severity of hearing loss without compromising survival (Fernandez et al, in press).