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Nanomechanics of inner-ear hair-cell transduction

内耳毛细胞转导的纳米力学

基本信息

批准号：
10539982
负责人：
Marcos Sotomayor
金额：
$ 37.74万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539982
关键词：
Aminoglycosides Animal Model Architecture Atomic Force Microscopy Binding Binding Proteins Brain CDH23 gene Cadherins Calcium Calcium Binding Calcium and Integrin Binding Protein 2 Cations Closure by clamp Complex Computational Technique Consensus Cryoelectron Microscopy Crystallization Dimerization Elasticity Electrophysiology (science)Equilibrium Event Extracellular Domain Filament Goals Hair Hair Cells Head Movements Hearing Homology Modeling Human Integral Membrane Protein Integrin Binding Ion Channel Ions Knockout Mice Labyrinth Length Link Lipids Mass Spectrum Analysis Mechanics Mechanoreceptor Cell Mediating Membrane Membrane Potentials Membrane Proteins Modeling Molecular Molecular Conformation Molecular Structure Mus Mutation N-terminal Nature Nuclear Magnetic Resonance PCDH15 gene Perception Pore Proteins Probability Process Property Protein Family Proteins Regulation Rest Role Sensory Sensory Disorders Set protein Signal Transduction Spectrum Analysis Speed Spottings Stretching Structural Models Structure Testing aminoglycoside-induced ototoxicity base biophysical analysis biophysical techniques cellular transduction computerized tools deafness dimer experimental study genetic deafness hearing impairment human model improved insight link protein mechanical force mechanical stimulus mechanotransduction member microscopic imaging molecular dynamics mutant nanomechanics potassium ion protein function response simulation sound vibration

项目摘要

PROJECT SUMMARY Vibrations from sound and mechanical stimuli from head movements are transformed into electrochemical signals for brain processing by inner-ear hair-cell mechanoreceptors mediating our senses of hearing and balance. Essential to hair-cell function are the proteins that form its mechanotransduction apparatus comprised of a fine tip-link filament that pulls on an ion channel complex to trigger sensory perception. The tip-link filament is formed by cadherin-23 (CDH23) and protocadherin-15 (PCDH15) proteins while the ion channel complex is thought to be formed by members of the transmembrane channel-like protein family TMC1 and TMC2, the transmembrane inner ear protein TMIE, and the tetraspan membrane protein of hair-cell stereocilia TMHS (also known as LHFPL5). In addition, the calcium and integrin binding protein CIB2 binds to TMC channels to regulate mechanotransduction. All these proteins are important for hearing and balance and are involved in inherited deafness, yet their molecular structures and the functional architecture of the transduction complex they form are poorly understood. The overall long-term goal of this project is to reveal the structural determinants of function for the proteins forming the inner-ear tip link and transduction ion channel complex. In Aim 1, we will use cryo-electron microscopy, high-speed atomic force microscopy, and molecular dynamics simulations to study the full-length extracellular domains of CDH23 and PCDH15 and thereby establish the structural determinants of tip-link function in inner ear mechanotransduction. In Aim 2, we will generate testable predictions using microsecond-long molecular dynamics simulations with biasing membrane potentials to characterize permeation of ions and ototoxic aminoglycosides through experimentally validated structural models of TMC protein pores. In Aim 3, we will use various computational and biophysical techniques, including nuclear magnetic resonance and native mass spectrometry, to explore regulatory mechanisms of transduction by CIB proteins. Results obtained from the proposed experiments and simulations will provide an initial and dynamic molecular view of the protein components of the inner ear mechanotransduction apparatus as we advance to understand its architecture and function in normal and impaired hearing and balance.

项目总结