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? Studies aimed at addressing the first question are focused on the basic science of cellular stress and the signal transduction pathways that are activated in response to stress. Studies of stress signaling suggest that cells under stress activate signal transduction pathways that will promote the cells survival while simultaneously activating pathways that will promote the cells death. It is often the balance (or imbalance) of these death vs. survival signals that determines whether the cell under stress ultimately lives or dies. Our studies are focused on the death and survival signals that are activated when hair cells are under stress. Currently we are examining the roles of heat shock proteins (HSPs) in promoting survival of hair cells under stress. Our studies demonstrate 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). Importantly, we find that pro-survival induction of HSP expression is relatively low in hair cells and is much more robust in surrounding glia-like supporting cells (May et al., 2013 J. Clinical Investigation 123(8):3577). These data indicate that hair cells may have a reduced capacity to induce pro-survival signaling in response to stress, and that supporting cells function as critical mediators of pro-survival signaling when hair cells are under stress. The second major question under study in our lab is translational: how do we develop clinical therapies that promote hair cell survival and function in order to preserve hearing in humans exposed to ototoxic drugs, noise trauma, or other hair cell stresses? Toward this goal we are examining methods of inducing HSPs in the cochlea. Our data using the pharmacological HSP inducer celastrol indicate that HSP induction inhibits ototoxic drug-induced hearing loss in mice receiving systemic injections of the aminoglycoside antibiotic kanamycin (Francis et al., 2011 Cell Death and Disease. 2, e195;doi:10.1038/cddis.2011.76). In order to restrict HSP induction to the inner ear, we have more recently examined the feasibility of using non-traumatic sound exposure to induce HSPs in the cochlea. Our data indicate that non-traumatic preconditioning sound can result in HSP induction in the cochleas of mice. Importantly, this preconditioning sound exposure inhibits hearing loss and hair cell death caused by systemic administration of either cisplatin or aminoglycosides (Roy, Ryals et al., 2013 J. Clinical Investigation 123(11):4945). These data indicate that preconditioning sound can protect the inner ear against ototoxic drug-induced hearing loss. An advantage of sound therapy is that it is unlikely to cause systemic side effects or to interfere with the therapeutic efficacy of either cisplatin or aminoglycosides. We are currently developing a strategy for testing whether preconditioning sound therapy can protect the inner ears of humans receiving ototoxic drugs.
| 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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