With the identification of prestin, an anion transporter (SLC26) family member, as the elusive lateral membrane motor protein of the outer hair cell (OHC), we are faced with the possibility of understanding how this single molecule can effect the mammal?s exquisite sense of hearing. We propose to target a focused set of aims, including 1) determining the role of a leakage conductance in prestin, distinct from its transporter pathway, in hearing and defining its structural basis; 2) determine the role of anion binding residues, and the influence of mechanical load in governing prestin?s frequency dependence; simultaneous measures of sensor charge movement (NLC), electromotility and evoked-forces are planned and 3) determine the structural components of pillars that link prestin to the underlying cytoskeleton, and confirming the importance of such links in hearing. In order to reach these goals, we will employ a host of genetic, electrophysiological, molecular biological and biochemical methods. We believe that the information that we obtain through these studies will aid in understanding how the OHC enables us to hear so well and in turn how we might combat pathologies of the OHC that afflict millions.

Public Health Relevance

With the identification of prestin, an anion transport family member, as the elusive lateral membrane motor protein of the outer hair cell (OHC), we are faced with the possibility of understanding how this single molecule can effect the mammal?s exquisite sense of hearing. To that end, we will focus on defining the structural basis of a newly found leakage pathway in prestin that we believe plays a key role in Cl- conductance along the lateral wall. We will also determine what protein structures in prestin may give rise to the motor?s frequency dependence, focusing on the role of an identified anion binding site within it transport pathway and mechanical influences. In addition, we seek to identify the molecular links between, prestin and the underlying cytoskeleton; an important area that has largely been neglected. We believe that our molecular dissections will aid in understanding how the OHC enables us to hear so well and in turn how we might combat pathologies of the OHC that afflict millions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC008130-09A1
Application #
9309972
Study Section
Special Emphasis Panel (ZRG1-IFCN-J (90)S)
Program Officer
Freeman, Nancy
Project Start
2007-01-01
Project End
2022-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
9
Fiscal Year
2017
Total Cost
$688,916
Indirect Cost
$277,623
Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bai, Jun-Ping; Moeini-Naghani, Iman; Zhong, Sheng et al. (2017) Current carried by the Slc26 family member prestin does not flow through the transporter pathway. Sci Rep 7:46619
Song, Lei; Santos-Sacchi, Joseph (2016) A Walkthrough of Nonlinear Capacitance Measurement of Outer Hair Cells. Methods Mol Biol 1427:501-12
Lv, Caixia; Stewart, William J; Akanyeti, Otar et al. (2016) Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels. Cell Rep 15:2784-95
Santos-Sacchi, Joseph; Song, Lei (2016) Chloride Anions Regulate Kinetics but Not Voltage-Sensor Qmax of the Solute Carrier SLC26a5. Biophys J 110:2551-2561
McKay, Sharen E; Yan, Wayne; Nouws, Jessica et al. (2015) Auditory Pathology in a Transgenic mtTFB1 Mouse Model of Mitochondrial Deafness. Am J Pathol 185:3132-40
Bian, Shumin; Navaratnam, Dhasakumar; Santos-Sacchi, Joseph (2013) Real time measures of prestin charge and fluorescence during plasma membrane trafficking reveal sub-tetrameric activity. PLoS One 8:e66078
Wu, T; Song, L; Shi, X et al. (2011) Effect of capsaicin on potassium conductance and electromotility of the guinea pig outer hair cell. Hear Res 272:117-24
Frucht, Corey S; Santos-Sacchi, Joseph; Navaratnam, Dhasakumar S (2011) MicroRNA181a plays a key role in hair cell regeneration in the avian auditory epithelium. Neurosci Lett 493:44-8
Frucht, Corey S; Uduman, Mohamed; Kleinstein, Steven H et al. (2011) Gene expression gradients along the tonotopic axis of the chicken auditory epithelium. J Assoc Res Otolaryngol 12:423-35
Frucht, Corey S; Uduman, Mohamed; Duke, Jamie L et al. (2010) Gene expression analysis of forskolin treated basilar papillae identifies microRNA181a as a mediator of proliferation. PLoS One 5:e11502

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