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Identifying Genes for Non-syndromic Recessive Deafness-A Collaborative Study

鉴定非综合征性隐性耳聋基因——一项合作研究

基本信息

批准号：
8457016
负责人：
Saima Riazuddin
金额：
$ 30.89万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457016
关键词：
Affect Age Apoptosis Apoptotic Biological Cell Line Cells Cessation of life Clinical Counseling Data Development Diagnosis Disease Early Diagnosis Epithelium Etiology Evaluation Experimental Designs Family Gene Expression Gene Proteins Genes Genetic Genetic Determinism Genetic Variation Goals Hearing Hearing Impaired Persons Human Individual Inherited Intervention Knockout Mice Knowledge Labyrinth Link Maps Measures Molecular Molecular Epidemiology Molecular Genetics Morphology Mutant Strains Mice Mutate Mutation Neurons Oxidative Stress Pathway interactions Population Population Heterogeneity Positioning Attribute Prevention Process Proteins Research Role Scientific Advances and Accomplishments Sensory Severities Structure Techniques Therapeutic Therapeutic Agents Therapeutic Intervention Variant Work Zebrafish base deafness disability embryo cell gene function hearing impairment improved insight interest methionine sulfoxide reductase mouse model mutant next generation sequencing novel positional cloning prevent recessive genetic trait spiral ganglion trait

项目摘要

DESCRIPTION (provided by applicant): Hearing loss is a genetically heterogeneous disorder that can occur at any age, with any degree of severity, and in any population. Worldwide, 1.33 per 1000 individuals are affected by prelingual severe or profound deafness. Eighty-six distinct recessive genetic loci (DFNB) have been linked to nonsyndromic hearing impairment. To date, however, only 38 mutated genes have been identified from the 86 loci. Thus, despite the significant role of genetic factors in the etiology of recessive deafness and the dramatic progress in mapping of the DFNB loci, much remains to be uncovered regarding the identification of the genes involved in the hearing process as well as the molecular and cellular basis of hearing impairment. Gaining such knowledge is pivotal for the advancement of clinical interventions, including early diagnosis and novel treatments. The major goals of this application are to identify and characterize three deafness genes (DFNB74, DFNB85 and DFNB94) through comprehensive and systematic genetic and functional analyses. In our preliminary data we have already identified the DFNB74 mutant gene (MSRB3) and have developed a knockout mouse model for characterization studies. In addition, we have identified and mapped two new deafness loci (DFNB85 and DFNB94) segregating among 19 human families, and we are positioned to identify the specific gene variants on both of these loci. The proposed experimental design includes two overall aims: In Aim 1 we will identify causative genes on two novel DFNB loci (DFNB85 and DFNB94) using next-generation sequencing. We will also determine the expression and localization of the proteins encoded by the newly identified genes in the inner ear. In Aim 2, we will fully characterize the function of the known gene (MSRB3, locus DFNB74) in the inner ear, using a mouse model. Our experimental approach in Aim 2, based on extensive preliminary data, is to define the consequences of loss of MSRB3 on inner ear function, morphology, oxidative stress, and expression of genes involved in the apoptotic pathway. Our studies proposed through these two aims will employ state-of-the art genetic, molecular, and cell biological techniques. We anticipate that the completion of these studies will identify and provide information about two new genes responsible for nonsyndromic hearing loss in humans, and elucidate the function of the recently identified MSRB3 gene in the inner ear This work will advance the scientific understanding of deafness and it will have important clinical impact by enabling improved genetic diagnosis, counseling and the development of therapeutic interventions.

描述（由申请人提供）：