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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DC003544-16
Application #
8651909
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Ealy, Megan; Meyer, Nicole C; Corchado, Johnny Cruz et al. (2014) Rare variants in BMP2 and BMP4 found in otosclerosis patients reduce Smad signaling. Otol Neurotol 35:395-400
Shearer, A Eliot; Eppsteiner, Robert W; Booth, Kevin T et al. (2014) Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet 95:445-53
Azaiez, Hela; Booth, Kevin T; Bu, Fengxiao et al. (2014) TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum Mutat 35:819-23
Brophy, Patrick D; Alasti, Fatemeh; Darbro, Benjamin W et al. (2013) Genome-wide copy number variation analysis of a Branchio-oto-renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes. Hum Genet 132:1339-50
Shearer, A Eliot; Black-Ziegelbein, E Ann; Hildebrand, Michael S et al. (2013) Advancing genetic testing for deafness with genomic technology. J Med Genet 50:627-34
Hildebrand, Michael S; Morin, Matias; Meyer, Nicole C et al. (2011) DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss. Hum Mutat 32:825-34
Sheffield, Abraham M; Gubbels, Samuel P; Hildebrand, Michael S et al. (2011) Viral vector tropism for supporting cells in the developing murine cochlea. Hear Res 277:28-36
Shearer, A Eliot; Hildebrand, Michael S; Sloan, Christina M et al. (2011) Deafness in the genomics era. Hear Res 282:1-9
Zheng, Jing; Miller, Katharine K; Yang, Tao et al. (2011) Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with alpha-tectorin and is mutated in autosomal dominant hearing loss (DFNA4). Proc Natl Acad Sci U S A 108:4218-23
Bazazzadegan, Niloofar; Sheffield, Abraham M; Sobhani, Masoomeh et al. (2011) Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss. Am J Med Genet A 155A:1202-11

Showing the most recent 10 out of 62 publications