MECHANISMS OF ACTION OF VOLATILE ANESTHETICS

描述：(改编自申请者的摘要)摩根博士建议 继续在他的实验室里使用基因操作 线虫作为研究挥发性物质作用机理的工具 麻醉剂。所采用的单一麻醉终点是C. 在麻醉剂存在的情况下的优雅。秀丽线虫被用作模特 系统最终实现理解的长期目标，在 分子水平，挥发性麻醉剂如何产生可逆性的 意识。 实验室之前的工作已经证明了两个基因的突变， UNC-79和UNC-80赋予麻醉剂独特的变化模式 线虫的敏感性，对大多数脂质都有超敏反应 可溶麻醉药和对麻醉药的敏感性很少或没有变化 较低的脂类溶解度。基因UNC-1的突变会导致正常的 氟烷敏感的UNC-79和UNC-80线虫将经历三次 对氟烷的抗药性。因此，到目前为止的工作表明，存在一个 影响麻醉敏感性的基因家族，遗传途径有 描述了对挥发分敏感性的控制顺序 线虫体内的麻醉剂，野生型基因UNC-1已被发现 生产一种对氟烷敏感的产品 动物。 某些基因的鉴定也已经完成(尽管有些 身份识别是暂定的)。UNC-79是一种糖蛋白，被认为是 与参与神经元活动的几种跨膜蛋白有关。 UNC-80被初步鉴定为糖苷酶。UNC-1包含两个 基因，一个是类胃素基因，另一个是神经钙素(蛋白质 调节跨膜离子通道功能的产品)。 目前四年提案的具体目标是完成 描述UNC-1基因，描述导致突变的类型 改变对挥发性麻醉剂的敏感性，并寻找起作用的突变 作为UNC-1的抑制者。这些具体目标的最终目标是 在模型系统中使用分子遗传学来了解挥发性 麻醉药的工作，合理设计改进的麻醉药与此 知识，并运用麻醉部位和作用机制的知识 作为分析意识本身本质的一个探索者。

DESCRIPTION: (Adapted from the applicant's abstract) Dr. Morgan proposes to continue on-going work in his laboratory using genetic manipulations of the nematode C. elegans as a tool to study the mechanism of action of volatile anesthetics. The single anesthetic end-point employed is immobility of C. elegans in the presence of anesthetic. C. elegans is employed as a model system to eventually achieve the long term goal of understanding, at the molecular level, how volatile anesthetics produce reversible loss of consciousness. Previous work in the laboratory has documented that mutations in two genes, unc-79 and unc-80, confer a unique pattern of change in anesthetic sensitivity in C. elegans , with a hypersensitivity found for the most lipid soluble anesthetics and less or no change in sensitivity to anesthetics of lower lipid solubility. Mutations in the gene unc-1 cause the normally halothane-sensitive unc-79 and unc-80 nematodes to undergo a three-fold resistance to halothane. Thus, work to date has shown that there is a family of genes that affect anesthetic sensitivity, a genetic pathway has been proposed that describes the order of control of sensitivity to volatile anesthetics in C. elegans , and the wild type gene unc-1 has been found to produce a product that is necessary for sensitivity to halothane in these animals. Identifications of certain genes have also been accomplished (although some identifications are tentative). unc-79 is a glycoprotein thought to be related to several transmembrane proteins involved in neuronal activity. unc-80 is tentatively identified as a glycosidase. unc-1 contains two genes, one a stomatin-like gene and the other a neurocalcin (the protein products of which modulate transmembrane ion channel function). The specific aims of the present 4 year proposal are to finish characterizing the unc-1 gene, characterize the types of mutations that lead to altered sensitivity to volatile anesthetics, and seek mutations that act as suppressors of unc-1. The eventual goals of these specific aims are to use molecular genetics in a model system to understand how volatile anesthetics work, rationally design improved anesthetics with this knowledge, and use the knowledge of anesthetic site and mechanism of action as a probe to analyze the nature of consciousness itself.