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 focused our basic science studies on the roles of secretory exosomes 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. In addition we have begun to identify the downstream signaling pathways that mediate the protective effects of exosomes. 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 potential for using the cholesterol-lowering drugs known as statins to reduce cisplatin-induced hearing loss. In preclinical studies we demonstrated that lovastatin significantly reduces cisplatin-induced hearing loss in mice. Clinical studies: We are examining the extent to which statins reduce cisplatin-induced hearing loss in humans. We are studying this both retrospectively and prospectively. We have ongoing retrospective studies in collaboration with the both University of Rochester Otolaryngology Department and Walter Reed National Military Medical Center to examine whether statins reduce cisplatin-induced hearing loss in adults with head and neck cancer. In addition we have an ongoing prospective study in which we are testing 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. This study is entitled Hearing Loss and the Effects of Statin Drugs in People With Head and Neck Squamous Cell Carcinoma Treated With Cisplatin Chemoradiation, and its ClinicalTrials.gov Identifier is NCT03225157.

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Deafness & Other Communication Disorders
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Steyger, Peter S; Cunningham, Lisa L; Esquivel, Carlos R et al. (2018) Editorial: Cellular Mechanisms of Ototoxicity. Front Cell Neurosci 12:75
Spielbauer, Katie; Cunningham, Lisa; Schmitt, Nicole (2018) PD-1 Inhibition Minimally Affects Cisplatin-Induced Toxicities in a Murine Model. Otolaryngol Head Neck Surg 159:343-346
Francis, Shimon P; Cunningham, Lisa L (2017) Non-autonomous Cellular Responses to Ototoxic Drug-Induced Stress and Death. Front Cell Neurosci 11:252
Cunningham, Lisa L; Tucci, Debara L (2017) Hearing Loss in Adults. N Engl J Med 377:2465-2473
Breglio, Andrew M; Rusheen, Aaron E; Shide, Eric D et al. (2017) Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nat Commun 8:1654
Isgrig, Kevin; Shteamer, Jack W; Belyantseva, Inna A et al. (2017) Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome. Mol Ther 25:780-791
Zhu, Bovey Z; Saleh, Jasmine; Isgrig, Kevin T et al. (2016) Hearing Loss after Round Window Surgery in Mice Is due to Middle Ear Effusion. Audiol Neurootol 21:356-364
Wang, Tian; Chai, Renjie; Kim, Grace S et al. (2015) Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nat Commun 6:6613
Chien, Wade W; Isgrig, Kevin; Roy, Soumen et al. (2015) Gene therapy restores hair cell stereocilia morphology in inner ears of deaf whirler mice. Mol Ther :
Monzack, E L; May, L A; Roy, S et al. (2015) Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death. Cell Death Differ 22:1995-2005

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