Molecular Basis of Sensory Transduction in C elegans

秀丽隐杆线虫感觉转导的分子基础

• 批准号: 7029700
• 负责人: Miriam B Goodman
• 金额: $ 35.58万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029700
• 关键词: Caenorhabditis elegans; Xenopus; afferent nerve; biological signal transduction; cytoskeleton; extracellular matrix; gene mutation; membrane channels; membrane potentials; membrane proteins; neural conduction; potassium channel; sensory receptors; touch

DESCRIPTION (provided by applicant): The long-term objective of the proposed work is to understand mechanisms of mechanotransduction. The ability to detect mechanical energy is essential for our senses of touch, hearing, and balance as well as for on-going regulation of posture, osmotic balance, and blood pressure. In recent years, classical and forward genetic approaches in nematodes, fruit flies, zebra fish, and mice have yielded a small, but expanding list of proteins needed for touch and hearing. However, it is not clear whether or not all of these proteins function in sensory mechanotransduction or, if so, how they might act in concert to convert mechanical energy into electrical signals in neurons. We propose to investigate the molecular physiology of touch-sensitive neurons in the nematode Caenorhabditis elegans. For several reasons, C. elegans is a nearly ideal animal for this research. Now, extensive collections of touch-insensitive mutants, powerful molecular-genetic tools, and an unparalleled description of nervous system anatomy, co-exist with the ability to record electrical signals from single, identified mechanosensory neurons. Newly discovered parallels in the physiology of C. elegans vertebrate touch-sensitive neurons significantly increase the value of C. elegans as a model system. In this proposal, we focus on two classes of mechanosensory neurons (nonciliated PLM neurons and ciliated ASH neurons). Electrophysiological recordings will be made from PLM and ASH in normal animals to determine how mechanotransduction differs in these distinct classes of mechanosensory cells (Aims #1A, 3A). We will determine the cellular function of proteins predicted to form sensory transduction channels and voltage-gated K channels by comparing sensory responses in wild type and mutant cells (AIMS 1A, 3B, & 3C). To investigate how cellular architecture contributes to force transfer, we will also record from mutant animals with defects in extracellular and intracellular structures (Aim 1B). Finally, we will express channels needed for PLM function in heterologous cells and determine how known accessory proteins regulate single channel activity (Aim 2). What is learned from these studies will clarify basic mechanisms of mechanotransduction and could improve the diagnosis and treatment of sensory neuropathies associated with both inherited and acquired diseases.

描述(由申请人提供)：拟议工作的长期目标是了解机械转导的机制。检测机械能的能力对我们的触觉、听觉和平衡以及对姿势、渗透平衡和血压的持续调节都是必不可少的。近年来，线虫、果蝇、斑马鱼和老鼠的经典和前沿遗传方法已经产生了一小部分但不断扩大的触觉和听力所需的蛋白质清单。然而，目前尚不清楚所有这些蛋白质是否都在感觉机械转导中发挥作用，如果是的话，它们如何协同作用将机械能转化为神经元中的电信号。我们建议研究线虫线虫触觉敏感神经元的分子生理学。出于几个原因，线虫是这项研究的近乎理想的动物。现在，大量的触摸不敏感突变体、强大的分子遗传学工具和对神经系统解剖的无与伦比的描述，与记录单个已识别的机械感觉神经元的电信号的能力共存。新发现的线虫脊椎动物触敏神经元生理学上的相似之处显著增加了线虫作为模式系统的价值。在这个方案中，我们关注两类机械感觉神经元(无纤毛的PLM神经元和纤毛的ASH神经元)。将用正常动物的PLM和ASH进行电生理记录，以确定机械转导在这些不同类别的机械感觉细胞中的不同(AIMS#1A，3A)。我们将通过比较野生型和突变型细胞的感觉反应来确定预测形成感觉转导通道和电压门控K通道的蛋白质的细胞功能(目标1A、3B和3C)。为了研究细胞结构如何对力传递做出贡献，我们还将记录具有细胞外和细胞内结构缺陷的突变动物(目标1B)。最后，我们将在异种细胞中表达PLM功能所需的通道，并确定已知的辅助蛋白如何调节单通道活动(目标2)。从这些研究中了解到的将阐明机械转导的基本机制，并可能改善与遗传性和获得性疾病相关的感觉神经病的诊断和治疗。