The long-term goal of my laboratory is to elucidate the mechanisms that control mechanoelectrical transduction (MET) in hair cells, and the defects in this process that cause deafness. We propose here to study the function of the cell adhesion molecules cadherin 23 (CDH23) and protocadherin 15 (PCDH15) in hair cell function and disease. Previous studies have shown that CDH23 and PCDH15 are required for hair bundle development. Recent findings show that CDH23 and PCDH15 are components of extracellular filaments that connect stereocilia not only in developing but also in functionally mature hair cells. Based on these findings and new preliminary data, we hypothesis that CDH23 and PCDH15 are components of larger transmembrane signaling complexes in hair cells that control not only hair bundle morphogenesis but also MET. We predict that alternative splicing regulates the assembly and function of these protein complexes. To test our hypothesis, we will: (i) Determine the function of CDH23 for MET using genetically modified mice that were designed to circumvent developmental hair cell defects that are associated with CDH23 null alleles;(ii) define the function of PCDH15 splice variants for hair cell development and MET;(iii) isolate by yeast-two-hybrid assays novel components of CDH23 and PCDH15 dependent adhesion complexes in hair cells;(iv) analyze mouse lines with mutations in CDH23 that mimic mutations in patients suffering from Usher Syndrome 1D and autosomal recessive deafness DFNB12. We anticipate that mutations that are associated with different disease phenotypes affects distinct aspects of CDH23 function in hair cells. Deafness is a major health problem. 1 in 1000 children is born with hearing impairment and large parts of the aging population are afflicted by age-related hearing loss. In recent years, dramatic progress has been made in identifying gene mutations that cause deafness, but we know comparatively little about the mechanisms by which mutations in the affected genes cause deafness. We propose here to study the function of two genes that have been linked to deafness, Cdh23 and Pcdh15, in hair cells. Based on published and preliminary data, we anticipate that the two genes are required both for the development and function of mechanosensory hair cells, and that different mutations in the two genes that cause syndromic and non-syndromic forms of deafness affect distinct aspects of gene function in hair cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005965-10
Application #
8277372
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2003-04-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$385,903
Indirect Cost
$182,260
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Zhao, Bo; Wu, Zizhen; Müller, Ulrich (2016) Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function. Elife 5:
Zeng, Wei-Zheng; Grillet, Nicolas; Dewey, James B et al. (2016) Neuroplastin Isoform Np55 Is Expressed in the Stereocilia of Outer Hair Cells and Required for Normal Outer Hair Cell Function. J Neurosci 36:9201-16
Wu, Zizhen; Müller, Ulrich (2016) Molecular Identity of the Mechanotransduction Channel in Hair Cells: Not Quiet There Yet. J Neurosci 36:10927-10934
Beurg, Maryline; Xiong, Wei; Zhao, Bo et al. (2015) Subunit determination of the conductance of hair-cell mechanotransducer channels. Proc Natl Acad Sci U S A 112:1589-94
Müller, Ulrich; Barr-Gillespie, Peter G (2015) New treatment options for hearing loss. Nat Rev Drug Discov 14:346-65
Zhao, Bo; Müller, Ulrich (2015) The elusive mechanotransduction machinery of hair cells. Curr Opin Neurobiol 34:172-9
Zhao, Bo; Wu, Zizhen; Grillet, Nicolas et al. (2014) TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron 84:954-67
Xiong, Wei; Wagner, Thomas; Yan, Linxuan et al. (2014) Using injectoporation to deliver genes to mechanosensory hair cells. Nat Protoc 9:2438-49
Kazmierczak, Piotr; Muller, Ulrich (2012) Sensing sound: molecules that orchestrate mechanotransduction by hair cells. Trends Neurosci 35:220-9
Xiong, Wei; Grillet, Nicolas; Elledge, Heather M et al. (2012) TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells. Cell 151:1283-95

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