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Integrative Structural and Functional Characterization of Tip-Link Cadherins Deafness

Tip-Link 钙粘蛋白耳聋的综合结构和功能表征

基本信息

批准号：
9502717
负责人：
Ulrich Mueller
金额：
$ 71.62万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2018-03-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9502717
关键词：
Adhesions Affect Age Attention Auditory Bacteria Binding Biochemical Biophysics CDH23 gene Cadherin Domain Cadherins Cell physiology Cells Child Cochlea Complex Crystallography Data Defect Development Dimerization Disease Disease Outcome Dissection Extracellular Domain Gene Mutation Genes Genetic Polymorphism Genetically Engineered Mouse Goals Hair Hair Cells Health Hearing Hearing Tests Image Imaging Device Impairment Inner Hair Cells Investigation Ion Channel Laboratories Labyrinth Lead Link Mammalian Cell Maps Mechanics Mediating Membrane Molecular Morphogenesis Mus Mutation Neurosciences Noise Noise-Induced Hearing Loss PCDH15 gene Pathogenesis Physiological Presbycusis Property Publishing Resolution Retinal Role Signal Transduction Structure Structure-Activity Relationship Surface Syndrome Testing Usher Syndrome Visual X-Ray Crystallography age related aging population base biochemical tools biophysical analysis congenital deafness deafness dimer early onset extracellular hearing impairment insight intermolecular interaction link protein loss of function mutation mechanotransduction member mutant neurotransmission particle protein complex protein structure reconstruction sound vibration

项目摘要

Deafness is a major health problem. A major cause of deafness is defects in hair cells, the mechanosensory cells of the cochlea that convert sound induced vibrations into electrical signals to provide our sense of hearing. Mutations in the genes encoding protocadherin (PCDH15) and cadherin 23 (CDH23) cause hearing loss. Both genes are expressed in the hair bundles of the mechanosensory hair cells of the inner ear where they form heterophilic adhesion complexes that are important for hair bundle morphogenesis and mechanotransduction. Significantly, different mutation in both PCDH15 and CDH23 lead to different disease outcomes. While some mutations cause profound congenital deafness with retinal impairment (Usher Syndrome) others lead to recessive and progressive hearing loss without visual involvement. Gene-association studies also suggest a link of CDH23 polymorphisms with age- and noise-induce hearing loss. The mechanisms by which different mutations lead to distinct disease outcomes are poorly defined. We propose here to combine high-resolution structural studies with functional studies in hair cells to gain insights into the mechanisms by which PCDH15 and CDH23 regulate hair cell function and to define disease mechanisms. To achieve this goal, a laboratory with expertise in studying the biophysical and structural properties of cadherins and a laboratory dedicated to the study of auditory neuroscience have combined their efforts to achieve what either could not accomplish alone. Unlike previous studies that have focused on structural analysis of small monomeric fragments of CDH23 and PCDH15 expressed in bacteria, the team proposed to define the high- resolution structure of natively assembled PCDH15-CDH23 complexes using crystallography and cryo-EM. Structural data will be validated biochemically and by functional interrogation of mutant cadherins in the physiologically relevant mechanosensory hair cells paying attention to mutations associated with disease. We anticipate that our studies will provide the first high-resolution native structure of any protein complex important for mechanotransduction and provide mechanistic insights into its functional properties and pathophysiological mechanisms that are associated with different forms of hearing impairment.

耳聋是一个主要的健康问题。耳聋的一个主要原因是毛细胞的缺陷，即机械感觉器官