Hearing loss affects 15-26% of the world's population and among the elderly is the most common neurological disability. Although the relative contributions of hereditary and environmental factors to age- related hearing loss are unknown, the majority of inherited late-onset deafness is autosomal dominant and non-syndromic (autosomal dominant non-syndromic hearing loss, ADNSHL). The long-term goals of our research are: a) to identify ADNSHL-causing genes to address gaps in our understanding of the molecular biology of hearing and deafness in the elderly;and, b) to explore novel habilitation options for hearing loss. During the prior granting period, we focused on specific aims to: 1) localize and clone genes that cause ADNSHL;2) expand phenotype-genotype studies to facilitate gene identification in small families;and 3) initiate experiments on RNA interference (RNAi) as a potential treatment for select types of hearing loss. In this competitive renewal, we will build on our past accomplishments by completing the following specific aims:
Specific Aim 1 : To identify novel deafness-causing genes in a cohort of 230 families segregating ADNSHL by using targeted sequence capture platforms and/or whole exome analysis followed by massively parallel sequencing and data analysis using a customized local deployment of the Galaxy bioinformatics web platform Specific Aim 2: To improve and validate the efficacy of RNAi as a therapeutic for the prevention of ADNSHL by: a) modifying the design of short hairpin RNA (shRNA) and artificial microRNA (miRNA) to enhance their potency in the Kcnq4+/dn mouse;and, b) testing RNAi in a second murine model of ADNSHL, the Tmc1 G411R mutant mouse The successful completion of these aims will have a major impact on our understanding of the biology of hearing and deafness and potentially on the treatment of some types of hearing loss.

Public Health Relevance

This competitive renewal is focused on two questions germane to autosomal dominant non-syndromic hearing loss: 1) the identification of novel deafness-causing genes;and, 2) the evaluation of RNA interference as a therapeutic to prevent hearing loss. The successful completion of these aims will have a major impact on our understanding of the biology of hearing and deafness and potentially on the treatment of some types of hearing loss.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
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University of Iowa
Schools of Medicine
Iowa City
United States
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Shibata, Seiji B; Ranum, Paul T; Moteki, Hideaki et al. (2016) RNA Interference Prevents Autosomal-Dominant Hearing Loss. Am J Hum Genet 98:1101-13
Taylor, Kyle R; Booth, Kevin T; Azaiez, Hela et al. (2016) Audioprofile Surfaces: The 21st Century Audiogram. Ann Otol Rhinol Laryngol 125:361-8
Moteki, Hideaki; Yoshimura, Hidekane; Azaiez, Hela et al. (2015) USH2 caused by GPR98 mutation diagnosed by massively parallel sequencing in advance of the occurrence of visual symptoms. Ann Otol Rhinol Laryngol 124 Suppl 1:123S-8S
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