Genome-Wide Analysis of Ion Channels Required For Mechanosensation

机械感觉所需离子通道的全基因组分析

• 批准号: 7708759
• 负责人: William D Tracey
• 金额: $ 23.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708759
• 关键词: Actins; Bacteria; Behavior; Caenorhabditis elegans; Cells; Complex; Data; Detection; Drosophila genome; Drosophila genus; Emergency Situation; Extracellular Matrix Proteins; Family; Genes; Goals; Hair Cells; Health; Homologous Gene; Human; Hypersensitivity; Individual; Ion Channel; Larva; Lead; Light; Mammals; Mechanical Stimulation; Mechanoreceptors; Membrane; Molecular; Neurons; Orthologous Gene; Osmotic Pressure; Pain; Pattern; Perception; Physiology; Play; RNA Interference; Role; Rupture; Stretching; System; Techniques; Testing; Time; Tissues; Touch sensation; Transcription Coactivator; Transgenic Organisms; Yeasts; base; cellular microvillus; deafness; epithelial Na+ channel; fly; genetic analysis; genome wide association study; genome-wide; genome-wide analysis; human disease; insight; interest; knock-down; mutant; neuronal excitability; novel; public health relevance; sensor

DESCRIPTION (provided by applicant): A large body of evidence suggests that ion channels act as force sensors in mechanotransduction systems. In flies, the No mechanoreceptor potential-C (Nomp-C) channel has been suggested to be a force transduction channel in neurons that detect bristle deflection. In C. elegans, mechanotransduction channels of the Deg/ENaC family have been unambiguously identified as force sensors in touch neurons. The Mec10/Mec4 channel is the central component of a transduction complex that also involves extracellular matrix proteins. In bacteria, a simpler form of mechanotransduction involves a mechanosensitive channel of large conductance (MscL) and another of smaller conductance (MscS). These bacterial force-sensing channels detect membrane stretch triggered by osmotic pressure and protect the cell from rupture by allowing emergency ejection of osmolytes. Despite progress in identifying these important channels, the identities of mechanotransduction channels in vertebrate neurons remain elusive. For example, orthologs of Nomp-C and Msc channels have not been found in mammals and there is limited evidence supporting a role for Deg/ENaC's in mammalian mechanotransduction. Since it is likely that molecular mechanisms of mechanotransduction are ancient, and evolutionarily conserved, we hypothesize that additional mechanotransduction channels have yet to be identified. The goal of this proposal is to identify candidates for these evolutionarily conserved mechanotransduction channels. To achieve this we will: 1) Test the hypothesis that predicted ion channel subunits of the Drosophila genome function in mechanotransduction by performing tissue-specific RNAi knock down of the ion channel RNAs in mechanosensory neurons. 2) Use optogenetic techniques to separate channels that are likely to act at the transduction step from those that function downstream of transduction. 3) Begin detailed genetic analysis of the mechanosensory ion channels that we have identified in the first two aims. Identifying the novel mechanotransduction channels and their vertebrate homologues may lead to an increased understanding of human diseases ranging from deafness to pain. PUBLIC HEALTH RELEVANCE: Identifying the novel mechanotransduction channels and their vertebrate homologues may lead to an increased understanding of human diseases ranging from deafness to pain.

描述（由申请人提供）：大量证据表明离子通道在机械转导系统中充当力传感器。在果蝇中，No mechanoreceptor potential-C （Nomp-C）通道被认为是神经元中检测刚毛偏转的力转导通道。在秀丽隐杆线虫中，Deg/ENaC家族的机械转导通道已被明确地确定为触觉神经元中的力传感器。Mec10/Mec4通道是一个转导复合体的核心组成部分，也涉及细胞外基质蛋白。在细菌中，一种更简单的机械传导形式包括一个大电导（MscL）和另一个小电导（MscS）的机械敏感通道。这些细菌力感应通道检测由渗透压触发的膜拉伸，并通过允许紧急喷射渗透液来保护细胞免于破裂。尽管在识别这些重要通道方面取得了进展，但脊椎动物神经元中机械转导通道的身份仍然难以捉摸。例如，在哺乳动物中尚未发现Nomp-C和Msc通道的同源物，并且支持Deg/ENaC在哺乳动物机械转导中的作用的证据有限。由于机械转导的分子机制很可能是古老的，并且在进化上是保守的，我们假设其他的机械转导通道尚未被确定。本提案的目标是确定这些进化上保守的机械转导通道的候选者。为了实现这一目标，我们将：1)通过执行组织特异性RNAi敲除机械感觉神经元中的离子通道rna来验证预测果蝇基因组离子通道亚基在机械转导中的功能的假设。2)使用光遗传学技术将可能在转导步骤中起作用的通道与转导下游的通道分开。3)开始对我们在前两个目标中确定的机械感觉离子通道进行详细的遗传分析。识别新的机械转导通道及其脊椎动物同源物可能会增加对从耳聋到疼痛等人类疾病的了解。公共卫生相关性：确定新的机械转导通道及其脊椎动物同源物可能会增加对从耳聋到疼痛等人类疾病的了解。