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)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC003544-15
Application #
8500957
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
Project Start
1998-08-01
Project End
2018-03-31
Budget Start
2013-04-12
Budget End
2014-03-31
Support Year
15
Fiscal Year
2013
Total Cost
$510,986
Indirect Cost
$130,721
Name
University of Iowa
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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
Jayawardena, Asitha D L; Shearer, A Eliot; Smith, Richard J H (2015) Sensorineural Hearing Loss: A Changing Paradigm for Its Evaluation. Otolaryngol Head Neck Surg 153:843-50
Mori, Kentaro; Moteki, Hideaki; Kobayashi, Yumiko et al. (2015) Mutations in LOXHD1 gene cause various types and severities of hearing loss. Ann Otol Rhinol Laryngol 124 Suppl 1:135S-41S
Moteki, Hideaki; Azaiez, Hela; Booth, Kevin T et al. (2015) Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation. Ann Otol Rhinol Laryngol 124 Suppl 1:177S-83S
Azaiez, Hela; Decker, Amanda R; Booth, Kevin T et al. (2015) HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice. PLoS Genet 11:e1005137
Shearer, A Eliot; Smith, Richard J H (2015) Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care. Otolaryngol Head Neck Surg 153:175-82
Sloan-Heggen, Christina M; Babanejad, Mojgan; Beheshtian, Maryam et al. (2015) Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran. J Med Genet 52:823-9
Elkon, Ran; Milon, Beatrice; Morrison, Laura et al. (2015) RFX transcription factors are essential for hearing in mice. Nat Commun 6:8549

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