Mouse models to study inherited forms of deafness

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DESCRIPTION (provided by applicant): 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.