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.
|Song, Yang; Milon, Beatrice; Ott, Sandra et al. (2018) A comparative analysis of library prep approaches for sequencing low input translatome samples. BMC Genomics 19:696|
|Milon, Béatrice; Mitra, Sunayana; Song, Yang et al. (2018) The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice. Biol Sex Differ 9:12|
|Imtiaz, Ayesha; Belyantseva, Inna A; Beirl, Alisha J et al. (2018) CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum Mol Genet 27:780-798|
|Yoshimura, Hidekane; Shibata, Seiji B; Ranum, Paul T et al. (2018) Enhanced viral-mediated cochlear gene delivery in adult mice by combining canal fenestration with round window membrane inoculation. Sci Rep 8:2980|
|Booth, Kevin T; Azaiez, Hela; Kahrizi, Kimia et al. (2018) Exonic mutations and exon skipping: Lessons learned from DFNA5. Hum Mutat 39:433-440|
|Matern, Maggie S; Beirl, Alisha; Ogawa, Yoko et al. (2018) Transcriptomic Profiling of Zebrafish Hair Cells Using RiboTag. Front Cell Dev Biol 6:47|
|Booth, K T; Kahrizi, K; Babanejad, M et al. (2018) Variants in CIB2 cause DFNB48 and not USH1J. Clin Genet 93:812-821|
|Booth, Kevin T; Kahrizi, Kimia; Najmabadi, Hossein et al. (2018) Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment. J Med Genet 55:555-560|
|Booth, Kevin T; Askew, James W; Talebizadeh, Zohreh et al. (2018) Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37. Genet Med :|
|Azaiez, Hela; Booth, Kevin T; Ephraim, Sean S et al. (2018) Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet 103:484-497|
Showing the most recent 10 out of 109 publications