Deflection of the sensory hair cell's hair bundle (mechanotransduction) results in an electrical response from the hair cell that is the primary signal for audition. Disruption of this pathway by noise, ototoxic agents or aging leads to maladies such as threshold shifts (both temporary and permanent), hearing loss, deafness at an extreme and may even underlie some forms of Tinnitus. Understanding the mechanisms involved in the mechanotransduction process should help identify sites for intervention and prevention of hearing loss and may also provide guidelines for development of replacement therapies such as hair cell regeneration. Although a great deal of knowledge regarding mechanotransduction has accrued over the past 25 years, many fundamental questions regarding mechanisms and functions remain to be elucidated. Experiments herein will use state of the art optical and electrical techniques coupled with tissue culture and pharmacological tools to probe several basic questions regarding hair cell mechanotransduction.
Specific Aim (SA) 1 will determine whether the functional mechano electric transduction (MET) channels are located at the tops or along the sides of the stereocilia by taking advantage of the morphological arrangement of inner hair cell bundles. It will determine the number of channels per stereocilia by coupling calcium imaging of individual stereocilia with measurements of MET current. Finally, it will determine the role of membrane tension on channel gating which should give insight into whether the MET channel is directly tethered to the tip-link or cytoskeleton or whether it is activated via membrane stretch. SA2 will investigate the Ca2+ dependence of adaptation and activation by coupling Ca2+ imaging, Ca2+ uncaging and electrophysiological measurements of MET currents. These experiments will attempt to separate calcium-dependent responses from mechanical stimulation and should yield important new kinetic information regarding the calcium regulation of transduction and adaptation. Experiments will also explore the Ca2+ dependence of hair bundle mechanics. SA3 will investigate single channel MET properties to determine the mechanism by which Ca2+ regulates channel conductance and open time. SA4 will test the hypothesis that MET provides mechanical tuning to the hair cell.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003896-15
Application #
8209183
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Cyr, Janet
Project Start
1999-01-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
15
Fiscal Year
2012
Total Cost
$553,735
Indirect Cost
$187,741
Name
Stanford University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Peng, Anthony W; Ricci, Anthony J (2011) Somatic motility and hair bundle mechanics, are both necessary for cochlear amplification? Hear Res 273:109-22
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Beurg, Maryline; Fettiplace, Robert; Nam, Jong-Hoon et al. (2009) Localization of inner hair cell mechanotransducer channels using high-speed calcium imaging. Nat Neurosci 12:553-8
Waguespack, Jessica; Salles, Felipe T; Kachar, Bechara et al. (2007) Stepwise morphological and functional maturation of mechanotransduction in rat outer hair cells. J Neurosci 27:13890-902
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Farris, Hamilton E; Wells, Gregg B; Ricci, Anthony J (2006) Steady-state adaptation of mechanotransduction modulates the resting potential of auditory hair cells, providing an assay for endolymph [Ca2+]. J Neurosci 26:12526-36

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