Abstract

Sensory hair cells are hypersensitive to death induced by noise, aging, and some therapeutic drugs. Two major classes of ototoxic drugs are the aminoglycoside antibiotics and the antineoplastic agent cisplatin. We plan to take advantage of a unique in vitro preparation of the adult mouse utricle that allows us to examine the rrechanisms underlying ototoxic hair cell death and survival at the molecular level. Understanding these cellular mechanisms will be critical for the design of therapies aimed at preventing or reversing hearing loss. The induction of heat shock proteins (HSPs) in response to cellular stress is a ubiquitous and highlyconserved response that can significantly inhibit apoptosis in some systems. Induction of HSPs occurs in hair cells in response to a variety of stimuli. However, there are no studies on the effects of HSPs on ototoxic drug-induced hair cell death. More importantly, there are no data available regarding the cellular interactions between HSPs and apoptotic proteins in hair cells in response to any stimulus. Our preliminary data demonstrate that in vitro heat shock treatment inhibits hair cell death in response to both neomycin and cisplatin exposure. The experiments in this proposal are designed to test the hypothesis that the protective effect of heat shock against ototoxic drug-induced hair cell death is the result of HSP-mediated inhibition of specific apoptotic signaling pathways. Four groups of experiments are proposed: 1). To examine the similarities and differences between the molecular mechanisms mediating cisplatin- vs. aminoglycoside-induced hair cell death. 2). To determine whether heat shock treatment is sufficient to induce a shift in the dose-response relationship between ototcxic drug concentration and hair cell survival. 3). To determine whether induction of HSP-70 is necessary and sufficient for the protective effect of heat shock against ototoxic hair cell apoptosis. 4). To investigate the interactions between HSPs and apoptotic proteins in hair cells exposed to ototoxic drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007613-04
Application #
7465453
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2005-07-15
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$341,586
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Pathology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425

  Publications

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
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
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 :
Francis, S P; Kramarenko, I I; Brandon, C S et al. (2011) Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32. Cell Death Dis 2:e195
Polesskaya, Oksana; Cunningham, Lisa L; Francis, Shimon P et al. (2010) Ablation of mixed lineage kinase 3 (Mlk3) does not inhibit ototoxicity induced by acoustic trauma or aminoglycoside exposure. Hear Res 270:21-7
Ou, Henry C; Cunningham, Lisa L; Francis, Shimon P et al. (2009) Identification of FDA-approved drugs and bioactives that protect hair cells in the zebrafish (Danio rerio) lateral line and mouse (Mus musculus) utricle. J Assoc Res Otolaryngol 10:191-203
Taleb, Mona; Brandon, Carlene S; Lee, Fu-Shing et al. (2009) Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death. Cell Stress Chaperones 14:427-37
Taleb, Mona; Brandon, Carlene S; Lee, Fu-Shing et al. (2008) Hsp70 inhibits aminoglycoside-induced hair cell death and is necessary for the protective effect of heat shock. J Assoc Res Otolaryngol 9:277-89
Chiu, Lynn L; Cunningham, Lisa L; Raible, David W et al. (2008) Using the zebrafish lateral line to screen for ototoxicity. J Assoc Res Otolaryngol 9:178-90
Cunningham, Lisa L (2006) The adult mouse utricle as an in vitro preparation for studies of ototoxic-drug-induced sensory hair cell death. Brain Res 1091:277-81

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