1) Studies aimed at understanding the molecular mechanisms underlying the protective effects of HSPs Our studies indicate that a mild heat stress induces a protective state in utricles. We are investigating the roles of heat shock protein 70 (HSP70) in mediating this protective effect. We find that HSP70 inhibits ototoxic hair cell death. Our recent data indicate that HSP70 is expressed in glia-like supporting cells that surround sensory hair cells. Supporting cells secrete HSP70, and this secreted HSP70 is capable of rescuing hair cells from death caused by ototoxic aminoglycoside antibiotics (May et al 2013 J. Clinical Investigation 123(8):3577). These data indicate that supporting cells are important determinants of whether a hair cell under stress ultimately lives or dies. 2) Studies aimed at translating our findings into clinical therapies to prevent hearing loss caused by exposure to ototoxic drugs An important goal of our studies is to 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. In order to restrict HSP induction to the inner ear, we have 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. In press). These data indicate that preconditioning sound can protect the inner ear against ototoxic drug-induced hearing loss in mice.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2013
Total Cost
$1,388,657
Indirect Cost
Name
National Institute on Deafness and Other Communication Disorders
Department
Type
DUNS #
City
State
Country
Zip Code
Baker, Tiffany G; Roy, Soumen; Brandon, Carlene S et al. (2015) Heat shock protein-mediated protection against Cisplatin-induced hair cell death. J Assoc Res Otolaryngol 16:67-80
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 :
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
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
Cunningham, Lisa L; Tucci, Debara L (2015) Restoring synaptic connections in the inner ear after noise damage. N Engl J Med 372:181-2
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 :
Chien, Wade W; Monzack, Elyssa L; McDougald, Devin S et al. (2014) Gene Therapy for Sensorineural Hearing Loss. Ear Hear :
May, Lindsey A; Kramarenko, Inga I; Brandon, Carlene S et al. (2013) Inner ear supporting cells protect hair cells by secreting HSP70. J Clin Invest 123:3577-87
Roy, Soumen; Ryals, Matthew M; Van den Bruele, Astrid Botty et al. (2013) Sound preconditioning therapy inhibits ototoxic hearing loss in mice. J Clin Invest 123:4945-9
Brandon, Carlene S; Voelkel-Johnson, Christina; May, Lindsey A et al. (2012) Dissection of adult mouse utricle and adenovirus-mediated supporting-cell infection. J Vis Exp :

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