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.
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.
|Booth, Kevin T; Azaiez, Hela; Kahrizi, Kimia et al. (2017) Exonic mutations and exon skipping: Lessons learned from DFNA5. Hum Mutat :|
|Korver, Anna M H; Smith, Richard J H; Van Camp, Guy et al. (2017) Congenital hearing loss. Nat Rev Dis Primers 3:16094|
|Matern, Maggie; Vijayakumar, Sarath; Margulies, Zachary et al. (2017) Gfi1Cre mice have early onset progressive hearing loss and induce recombination in numerous inner ear non-hair cells. Sci Rep 7:42079|
|Michel, Vincent; Booth, Kevin T; Patni, Pranav et al. (2017) CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. EMBO Mol Med 9:1711-1731|
|Ortlip, Timothy E; Drake, Virginia E; Raghavan, Prashant et al. (2017) Inflammatory Pseudotumor of the Temporal Bone: A Case Series. Otol Neurotol 38:1024-1031|
|Booth, K T; Kahrizi, K; Babanejad, M et al. (2017) Variants in CIB2 cause DFNB48 and not USH1J. Clin Genet :|
|Shearer, A Eliot; Eppsteiner, Robert W; Frees, Kathy et al. (2017) Genetic variants in the peripheral auditory system significantly affect adult cochlear implant performance. Hear Res 348:138-142|
|Shibata, Seiji B; Ranum, Paul T; Moteki, Hideaki et al. (2016) RNA Interference Prevents Autosomal-Dominant Hearing Loss. Am J Hum Genet 98:1101-1113|
|Beheshtian, Maryam; Babanejad, Mojgan; Azaiez, Hela et al. (2016) Heterogeneity of Hereditary Hearing Loss in Iran: a Comprehensive Review. Arch Iran Med 19:720-728|
|Sloan-Heggen, Christina M; Smith, Richard J H (2016) Navigating genetic diagnostics in patients with hearing loss. Curr Opin Pediatr 28:705-712|
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