The organ of Corti is composed of a variety of cell types including sensory, supporting and neural elements. Taken together, these cells comprise a functionally intricate and cohesive electrical unit that initiates the analysis of acoustic information within our environment. This electrical unit is extremely complex and nearly anatomically inaccessible, making an analysis of the whole quite a challenge. Fortunately, during the last several years the in vitro approach, including the isolated cochlea and cell preparations, has aided in the elucidation of cell function;the strategy is to understand the cells first on an individual basis, and finally to integrate this knowledge into a complete understanding of the organ of Corti. The overall aim of this project is to analyze the membrane properties of the outer hair cell (OHC), one of the major players in auditory function, principally using variations on the whole cell voltage and current clamp technique. We intend to 1) study characteristics of the OHC membrane that may impact on its motor performance, 2) study the chloride dependent allosteric modulation of the OHC motor and 3) study the developmental changes in the motor's biophysical sensitivities. I believe that the timely evaluation of these three specific research aims will help us appreciate key elements contributing to peripheral auditory system performance.

Public Health Relevance

With the identification of prestin 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 affect the mammal's exquisite sense of hearing. To that end, we have focused our interest on determining how allosteric modulation of the motor may give rise to the motor's known biophysical attributes, and how the motor matures during development. We hypothesize that understanding these molecular activities 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 #
5R01DC000273-32
Application #
8643196
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
1984-02-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
32
Fiscal Year
2014
Total Cost
$421,782
Indirect Cost
$166,929
Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Santos-Sacchi, Joseph; Song, Lei (2016) Chloride Anions Regulate Kinetics but Not Voltage-Sensor Qmax of the Solute Carrier SLC26a5. Biophys J 110:2551-61
Santos-Sacchi, Joseph; Song, Lei (2014) Chloride-driven electromechanical phase lags at acoustic frequencies are generated by SLC26a5, the outer hair cell motor protein. Biophys J 107:126-33
Santos-Sacchi, Joseph; Song, Lei (2014) Chloride and salicylate influence prestin-dependent specific membrane capacitance: support for the area motor model. J Biol Chem 289:10823-30
Ricci, Anthony J; Bai, Jun-Ping; Song, Lei et al. (2013) Patch-clamp recordings from lateral line neuromast hair cells of the living zebrafish. J Neurosci 33:3131-4
Song, Lei; Santos-Sacchi, Joseph (2013) Disparities in voltage-sensor charge and electromotility imply slow chloride-driven state transitions in the solute carrier SLC26a5. Proc Natl Acad Sci U S A 110:3883-8
Okunade, Oluwarotimi; Santos-Sacchi, Joseph (2013) IR laser-induced perturbations of the voltage-dependent solute carrier protein SLC26a5. Biophys J 105:1822-8
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
Raimundo, Nuno; Song, Lei; Shutt, Timothy E et al. (2012) Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. Cell 148:716-26
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
Bai, Jun-Ping; Surguchev, Alexei; Ogando, Yudelca et al. (2010) Prestin surface expression and activity are augmented by interaction with MAP1S, a microtubule-associated protein. J Biol Chem 285:20834-43

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