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Functions of Fam65b protein complex at the basal stereocilia in hearing and deafness

基底静纤毛 Fam65b 蛋白复合物在听力和耳聋中的功能

基本信息

批准号：
10433855
负责人：
Bo Zhao
金额：
$ 39.38万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10433855
关键词：
Actins Affect Apical Auditory Perception Biochemical Pathway CRISPR/Cas technology Cell physiology Cell surface Child Cochlea Complex Cytoskeleton Data Defect Disease Epithelial Event Generations Genes Genetic Genomics Goals Hair Cells Health Hearing Human Individual Libraries Link Location Maintenance Maps Mechanics Microfilaments Molecular Morbidity - disease rate Morphogenesis Morphology Mus Mutant Strains Mice Mutation Names Nervous system structure Outcome Pathology Pathway interactions Process Property Proteins Quality of life Regulation Research Role Sensorineural Hearing Loss Sensory Shapes Signal Transduction Site Stimulus Surface System Testing Yeasts base crosslink cysteine rich protein deafness glutaredoxin hearing impairment insight link protein mechanotransduction mouse model mutant novel protein complex protein function sensor sound therapeutic development yeast two hybrid system

项目摘要

PROJECT SUMMARY/ABSTRACT Hearing loss is a leading cause of morbidity in children affecting about 2 to 3 out of every 1,000 individuals in the USA. While the study of affected genes has shed important insights into the mechanisms, we are just at the beginning to understand the disease mechanisms underlying morphogenetic events. The overall goal of this research is to elucidate the mechanisms that regulate the formation and maintenance of the stereociliary bundle of cochlear hair cells, and the defects in this process that cause deafness. We propose to investigate the functions of Fam65b protein complex in the cochlear hair cells and auditory perceptions. In our preliminary studies, we have identified several components in the Fam65b protein complex. We have generated genomic modified mouse models using CRISPR/Cas9 system. We have employed immunostaining and illustrated the stereociliary defects in these mice. Based on our preliminary data, we hypothesize that Fam65b protein complex is critical for the structural organization of stereociliary bundle of cochlear hair cells. To test our hypothesis, we will: i) Functionally characterize proteins in the Fam65b protein complex localized at the basal region of stereocilia; ii) Characterize the biochemical pathways by which Fam65b protein complex regulate hair cell function and determine the extent to which they modulate the actin cytoskeleton in stereocilia; iii) Continue our identification of hair cell proteins in the Fam65b protein complex. Our preliminary data show the feasibility of our approach. We anticipate that our studies will shed new insights into the molecular machinery that shapes stereocilia and determines its properties. Quite possibly, our findings may link several deafness-related genes into a common molecular pathway and provide new leads for the development of therapeutic approaches for the treatment of some forms of the disease.

项目总结/文摘