The purpose of this proposal is to further our understanding of outer hair cell (OHC) function. Since these sensory receptor cells are required for normal sensitivity and frequency selectivity, it is important to define the protein networks involved in establishing these essential features of peripheral signal processing. It is known that OHC physiology is modulated by efferent signals originating in the medial olivocochlear (MOC) pathway (Guinan, 1996). In response to the release of acetylcholine (ACh), intracellular calcium increases and the subsequent outflow of potassium hyperpolarizes the cell. This change in membrane potential is thought to adjust the cochlear amplifier. Additional calcium-associated events and protein phosphorylation are likely to underlie changes in the cytoskeleton and in prestin, the OHC's motor protein. An influence on mechanoelectrical transduction (MET) in the stereocilia is also implicated. Speculation suggests that slow aspects of these changes are important for protecting OHCs at high sound levels. The fast changes, however, are thought to improve hearing in noise. Although studied for well over 50 years (Rasmussen, 1946;Galambos, 1956), the mechanisms underlying these changes are largely hypothetical. We are, therefore using various genetically altered mice to define the protein networks comprising this mechanical feedback loop. The use of mice with altered cytoskeleton, missing or nonfunctional prestin, defects in calcium-binding proteins and malfunction in various aspects of MET, will allow us to characterize cellular components associated with both fast and slow aspects of OHC modulation associated with activation of the MOC pathway. By combining measurements of basilar membrane mechanics and cochlear potentials with in vitro OHC and molecular analysis, it is possible to learn which mechanisms are required for changes in OHC function on both fast and slow time scales.

Public Health Relevance

Of the well over 30 million people in the US with auditory problems, the vast majority have defects in outer hair cell (OHC) function. These sensory receptor cells within the cochlea are required for normal sensitivity and frequency selectivity. Because their loss or malfunction results in major processing difficulties, our work on both normal and genetically altered OHCs is required in order to improve clinical outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
3R01DC000089-41A1S1
Application #
8366895
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
1991-01-01
Project End
2016-08-31
Budget Start
2011-09-21
Budget End
2012-08-31
Support Year
41
Fiscal Year
2012
Total Cost
$2,135
Indirect Cost
$735
Name
Northwestern University at Chicago
Department
Other Health Professions
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Wiwatpanit, Teerawat; Lorenzen, Sarah M; CantĂș, Jorge A et al. (2018) Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature 563:691-695
Takahashi, Satoe; Sun, Willy; Zhou, Yingjie et al. (2018) Prestin Contributes to Membrane Compartmentalization and Is Required for Normal Innervation of Outer Hair Cells. Front Cell Neurosci 12:211
Wiwatpanit, Teerawat; Remis, Natalie N; Ahmad, Aisha et al. (2018) Codeficiency of Lysosomal Mucolipins 3 and 1 in Cochlear Hair Cells Diminishes Outer Hair Cell Longevity and Accelerates Age-Related Hearing Loss. J Neurosci 38:3177-3189
Xu, Yingyue; Cheatham, Mary Ann; Siegel, Jonathan H (2017) Identifying the Origin of Effects of Contralateral Noise on Transient Evoked Otoacoustic Emissions in Unanesthetized Mice. J Assoc Res Otolaryngol 18:543-553
Takahashi, Satoe; Homma, Kazuaki; Zhou, Yingjie et al. (2016) Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-?-cyclodextrine is prestin-dependent. Sci Rep 6:21973
Takahashi, Satoe; Cheatham, Mary Ann; Zheng, Jing et al. (2016) The R130S mutation significantly affects the function of prestin, the outer hair cell motor protein. J Mol Med (Berl) 94:1053-62
Cheatham, Mary Ann; Ahmad, Aisha; Zhou, Yingjie et al. (2016) Increased Spontaneous Otoacoustic Emissions in Mice with a Detached Tectorial Membrane. J Assoc Res Otolaryngol 17:81-8
Cheatham, Mary Ann; Edge, Roxanne M; Homma, Kazuaki et al. (2015) Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in PrestinV499G/Y501H Knockin Mice. PLoS One 10:e0145428
Keller, Jacob Pearson; Homma, Kazuaki; Duan, Chongwen et al. (2014) Functional regulation of the SLC26-family protein prestin by calcium/calmodulin. J Neurosci 34:1325-32
Homma, Kazuaki; Duan, Chongwen; Zheng, Jing et al. (2013) The V499G/Y501H mutation impairs fast motor kinetics of prestin and has significance for defining functional independence of individual prestin subunits. J Biol Chem 288:2452-63

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