MECHANOTRANSDUCING COMPLEXES IN C ELEGANS

线虫中的机械传导复合物

• 批准号: 6188135
• 负责人: MONICA A. DRISCOLL
• 金额: $ 21.01万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-08 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188135
• 关键词: Caenorhabditis elegans; alleles; animal genetic material tag; behavioral /social science research tag; biological models; biological signal transduction; cytoskeleton; ethology; gene deletion mutation; mechanoreceptors; model design /development; molecular cloning; neural information processing; proprioception /kinesthesia; protein structure function; receptor expression; recombinant proteins; sodium channel; touch

DESCRIPTION: Mechanical forces such as focused pressure or membrane stretch play central, but poorly understood, roles in biology. What types of molecules mediate mechanical signaling? Elegant electrophysiological studies have implicated a class of mechanically-gated ion channels in mechanotransduction. A recent breakthrough in this field is that analyses of C. elegans have identified members of a family of eukaryotic ion channels postulated to play central roles in mechanical signaling. In specialized touch sensory neurons, MEC-4 and MEC-10 channel subunits mediate touch transduction. A related subunit, UNC-8, modulates locomotion and is proposed to be involved in nematode proprioception (how an organism maintains a sense of where its different parts are and coordinates their motions). The identification of candidate mechanically-gated channels in C. elegans has now laid the groundwork for deciphering molecular mechanisms of mechanical signaling. Here the principal investigator proposes to combine genetic, molecular and biochemical approaches to deduce the molecular compositions and identify regulators of two mechanosensitive complexes. The specific goals are: 1) to test and extend models of channel/cytoskeleton interaction by defining protein interactions mediated by MEC-4 and MEC-10 intracellular domains; 2) to characterize the UNC-8 candidate proprioception channel by identification of subcellular localization, cellular site of action, and additional channel subunits; and 3) to clone and characterize 4 identified loci that genetically interact with unc-8 and to deduce the mechanisms by which they influence UNC-8 channel function. This work will test, refine and extend working models for molecular mechanisms of mechanotransduction, a significant issue because so little is understood of mechanical signaling and so many biological processes (ranging from cell volume regulation to the senses of touch, hearing and balance) depend upon it. In addition, the MEC-4/MEC-10 and UNC-8 channels are related to human ENaC channels that mediate Na+ readsorption and are essential for maintenance of electrolyte balance, blood pressure regulation, and clearing of fluid from neonatal lungs. Analyses of nematode and mammalian channels to date indicates that they work in fundamentally similar ways and thus data we generate in this work from a unique experimental perspective are expected to provide similar insight into general working of the channel class and hold implications for betterment of human health.

描述：诸如聚焦压力或膜拉伸之类的机械力 在生物学中发挥中心作用，但知之甚少。 什么类型 分子介导机械信号传导？ 优雅的电生理学 研究牵涉到一类机械门控的离子通道 机械转导。 该领域最近的一个突破是分析 秀丽隐杆线虫已经确定了真核生物离子通道家族的成员 假设在机械信号中起着核心作用。 在专业中 触摸感官神经元，MEC-4和MEC-10通道亚基中介触摸 转导。 相关亚基UNC-8调节运动，IS 提议参与线虫的本体感受（生物如何 保持对不同部分的位置的感觉，并协调他们的 动议）。 在秀丽隐杆线虫中识别候选机械门控通道 现在已经为解密的分子机制奠定了基础 机械信号传导。 在这里，主要研究人员建议将 遗传，分子和生化方法推断分子 组成并识别两个机械敏感复合物的调节剂。 这 具体目标是：1）测试和扩展通道/细胞骨架的模型 通过定义由MEC-4和MEC-10介导的蛋白质相互作用的相互作用 细胞内结构域； 2）表征UNC-8候选本体感受 通过鉴定亚细胞定位，蜂窝位点 动作和其他频道亚基； 3）克隆和特征4 鉴定出与UNC-8相互作用并推断出遗传相互作用的基因座 它们影响UNC-8通道功能的机制。 这项工作将测试，完善并扩展分子的工作模型 机械转导的机制，这是一个重大问题，因为很少 了解机械信号传导和许多生物学过程（范围 从细胞体积调节到触摸，听力和平衡的感觉） 取决于它。 此外，MEC-4/MEC-10和UNC-8通道是 与介导Na+读取的人类ENAC通道有关，并且 维持电解质平衡，血压调节至关重要， 并清除新生儿肺部的液体。 线虫和 迄今为止的哺乳动物渠道表明它们在根本上工作 我们从独特的实验中在这项工作中生成的方法和数据 期望观点对一般工作的类似见解 渠道类并具有改善人类健康的影响。