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. These data indicate that supporting cells are critical determinants of the fate of a stressed or damaged sensory hair cell. This year we have examined whether HSP70 is secreted in (or on) secretory exosomes. Exosomes are endosomally-derived extracellular vesicles that are released from many cell types. They carry protein and nucleic acid cargo that can alter cellular functions in recipient cells. We have shown that exosomes are released from heat-shocked utricles, and that some cell-line derived exosomes can reduce ototoxic drug-induced hair cell death in vitro. We are currently examining the mechanisms by which exosomes facilitate intercellular communication in the inner ear. 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 examining methods of inducing HSPs in the cochlea. Potential approaches to this include pharmacological HSP induction, noise stress, and heat stress. In another set of translational studies, we have recently examined cisplatin pharmacokinetics in the mouse and human inner ears. Our data indicate that while cisplatin is efficiently eliminated from most tissues, it accumulates and remains in the cochlea with very slow clearance. These findings challenge the idea that the inner ear is uniquely sensitive to cisplatin, suggesting instead that the inner ear may experience a higher cumulative exposure to the drug. Clinical studies: We performed a retrospective study in collaboration with the University of Rochester Otolaryngology Department to examine the potential for statins (the cholesterol-lowering drugs) to reduce cisplatin-induced hearing loss in adults with head and neck cancer. The results of that study served as pilot data in the design of a prospective clinical study in patients undergoing cisplatin therapy for head and neck cancer to determine whether individuals taking statins experience less cisplatin-induced hearing loss than those not taking statins.
| 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 |
| 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 |
| Drummond, Meghan C; Barzik, Melanie; Bird, Jonathan E et al. (2015) Live-cell imaging of actin dynamics reveals mechanisms of stereocilia length regulation in the inner ear. Nat Commun 6:6873 |
| Chien, Wade W; McDougald, Devin S; Roy, Soumen et al. (2015) Cochlear gene transfer mediated by adeno-associated virus: Comparison of two surgical approaches. Laryngoscope : |
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