Deafness is a major health problem. ~1 in 1000 children is born deaf and a large part of the aging population is afflicted by age-related hearing loss. Many forms of deafness are of genetic origin, but only a subset of the genes that are linked to deafness have been identified. There is also a pressing need for animal models to study gene function in the auditory system, to define the molecular pathogenesis of hearing loss, and to develop therapeutic approaches for treating deafness. The long-term goal of my laboratory is to elucidate the molecular mechanisms that control sound perception and the defects in this process that cause deafness. As a first step towards attaining this goal, we propose to carry out a ENU mutagenesis screen in mice to identify and study genes that control the development and function of the auditory system. We hypothesize that we will obtain valuable mouse models for analyzing the mechanisms that control auditory processing and for defining the molecular pathogenesis of deafness in humans. The hypothesis is based on the following data: i) mutations in orthologous genes frequently cause deafness in humans and mice; ii) ENU mutagenesis screens in mice for deafness traits have provided useful animal models for studying dominant forms of deafness in humans; iii) we have carried out an ENU mutagenesis screen to identify recessive and dominant deafness traits; we have identified 20 mouse strains that are deaf; iv) we have identified a novel allele of the cadherin 23 (CDH23) gene, a known deafness locus in humans; v) The cloning of additional deafness loci is nearing completion. Some of the chromosomal regions that we have identified have not been previously associated with deafness. We predict to identify novel genes that are associated with deafness.To reach the overall goal of this proposal, we have established a collaboration with Dr. R. Smith (University of Iowa) to analyze the extent to which mutations in human orthologs of the mouse genes cause deafness.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007704-04
Application #
7433238
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$390,158
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Wu, Zizhen; Grillet, Nicolas; Zhao, Bo et al. (2017) Mechanosensory hair cells express two molecularly distinct mechanotransduction channels. Nat Neurosci 20:24-33
Harris, Suzan L; Kazmierczak, Marcin; Pangrši?, Tina et al. (2017) Conditional deletion of pejvakin in adult outer hair cells causes progressive hearing loss in mice. Neuroscience 344:380-393
Kazmierczak, Marcin; Kazmierczak, Piotr; Peng, Anthony W et al. (2017) Pejvakin, a Candidate Stereociliary Rootlet Protein, Regulates Hair Cell Function in a Cell-Autonomous Manner. J Neurosci 37:3447-3464
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
Zhao, Bo; Müller, Ulrich (2015) The elusive mechanotransduction machinery of hair cells. Curr Opin Neurobiol 34:172-9
Müller, Ulrich; Barr-Gillespie, Peter G (2015) New treatment options for hearing loss. Nat Rev Drug Discov 14:346-65
Kazmierczak, Marcin; Harris, Suzan L; Kazmierczak, Piotr et al. (2015) Progressive Hearing Loss in Mice Carrying a Mutation in Usp53. J Neurosci 35:15582-98
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

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