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 hearing loss are of genetic origin, but the majority of genes that are linked to the disease still need to be identified. There is also a pressing need for animal models to study gene function in the auditory system and to develop therapeutic approaches for treating hearing loss. 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 hearing loss. As a step towards attaining this goal, we propose here to extend our forward genetic screen in mice that was initiated in the previous funding period with the aim to generate mouse lines afflicted with congenital deafness. We have in the meantime optimized our screen and hypothesize that it will provide valuable animal models for studying the molecular pathogenesis of congenital, progressive, and late-onset forms of hearing loss in humans. This hypothesis is based on our published and preliminary data, which show that we have already generated in our screen mouse lines afflicted with various forms of hearing loss caused by mutations in genes linked to the human disease. To achieve our overall goal, we will generate by ENU mutagenesis additional mouse lines with hearing impairment, positionally clone the affected genes, characterize the mice phenotypically and search for mutation in human genes orthologous to the mouse genes that we identify in our screen. As more than 60% of the genes that are linked to hearing loss still need to be identified, we anticipate that we will identify additional genes that are linked to hearing loss in humans and generate mouse models for the human disease. Our mouse lines will be valuable for testing therapeutic approaches towards treating hearing loss.

Public Health Relevance

Hearing loss is a major health problem and frequently of genetic origin, but the majority of genes that are linked to the disease is not known. We propose here to generate by mutagenesis mouse models with defects in auditory function to identify gene mutations that cause deafness. We will determine the extent to which mutations in human genes orthologous to the mouse genes affect hearing and study disease mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007704-07
Application #
8092882
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2005-07-01
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
7
Fiscal Year
2011
Total Cost
$595,448
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
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
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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