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 two specific HSPs (HSP70 and HSP32) as mediators of this protective effect. We find that each of these molecules inhibits ototoxic hair cell death. In addition, both of these molecules inhibit activation of pro-apoptotic c-Jun N-terminal kinase (JNK) in hair cells treated with aminoglycosides. We are currently examining which cell types in the inner ear respond to stress by upregulating HSP70 and HSP32. 2) Studies aimed at translating our findings into clinical therapies to prevent hearing loss caused by exposure to ototoxic drugs We have recently shown that a pharmacological HSP inducer called celastrol inhibits aminoglycoside-induced hair cell death and hearing loss in mice. We also showed that the mechanism underlying celastrols protective effect is via induction of HSP32. We are currently examining additional methods of inducing HSPs in the inner ear with the goal of developing a co-therapy that will protect the hearing of human patients receiving ototoxic drugs. I arrived at NIH as a Tenure-track Investigator in January 2011. I have spent a significant portion of 2011 staffing the laboratory and ordering equipment.

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Support Year
1
Fiscal Year
2011
Total Cost
$1,866,250
Indirect Cost
Name
National Institute on Deafness and Other Communication Disorders
Department
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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
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Cunningham, Lisa L; Tucci, Debara L (2015) Restoring synaptic connections in the inner ear after noise damage. N Engl J Med 372:181-2
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
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

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