Research in the Section on Sensory Cell Biology is focused on mechanosensory hair cells, which are the receptor cells of hearing and balance. Sensory hair cells transduce sound energy or head movement into neural input to the brain. Hair cells are sensitive to death from a variety of stresses, including noise trauma, aging, certain genetic mutations, and exposure to therapeutic drugs with ototoxic side effects. While hair cell death is followed by robust regeneration that restores hearing and balance function in non-mammalian vertebrates, the capacity for hair cell regeneration is extremely limited in the mature mammalian inner ear. Thus hair cell death in mammals results in permanent hearing loss and/or balance disturbances. Our basic science studies are designed to examine the mechanisms that underlie sensory hair cell death and survival. Our translational studies are designed to use this mechanistic knowledge to guide the rational design of therapies aimed at preventing or reversing hearing loss in humans. Two major questions are currently being studied in the Section on Sensory Cell Biology: 1. What are the cellular and molecular signals that determine whether a hair cell under stress lives or dies? 2. How can we translate these survival vs. death signals into clinical therapies to prevent hearing loss? In the first group of studies, 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 ear 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 protein cargo of these protective exosomes in collaboration with D. Eric Anderson at NIDDK. Our data suggest that exosomes may represent a novel and important mechanism of intercellular communication in the inner ear. Our studies aimed at developing clinical therapies to reduce hearing loss currently include 1) preclinical studies aimed at optimizing sound therapy to reduce cisplatin-induced hearing loss, and 2) studies aimed at determining if FDA-approved drugs reduce cisplatin-induced hearing loss in animal models. We recently hired a staff scientist, Katharine Fernandez, AuD, PhD, who has now replicated our original sound-induced protection study and begun examining the feasibility of initiating a clinical trial to test if sound therapy can reduce cisplatin-induced hearing loss in humans. In addition Dr. Fernandez has 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.
| 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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