MECHANISMS OF ACTION OF VOLATILE ANESTHETICS

描述：（改编自申请人摘要）Morgan博士建议 继续在他的实验室进行的工作，使用基因操作的 线虫C.作为研究挥发性药物作用机制的工具 麻醉剂 采用的单一麻醉终点是C。 在麻醉剂的存在下。 C. elegans被用作模型 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的 意识 实验室先前的工作已经证明了两个基因的突变， UNC-79和UNC-80赋予麻醉剂的独特变化模式， 敏感性C。elegans，发现对大多数脂质 可溶性麻醉剂，对麻醉剂的敏感性变化较小或没有变化， 较低的脂溶性。 基因unc-1的突变导致正常的 对氟烷敏感的UNC-79和UNC-80线虫经历了三重 对氟烷的耐受性。 因此，迄今为止的工作表明， 影响麻醉剂敏感性的基因家族，一种遗传途径， 已经提出，描述了控制挥发性的敏感性的顺序， C.已发现野生型基因unc-1 生产一种产品，这是必要的敏感性，以氟烷在这些 动物 某些基因的鉴定也已经完成（尽管一些 鉴定是暂时的）。 UNC-79是一种糖蛋白， 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，一个是气孔蛋白样基因，另一个是神经钙蛋白（ 其产物调节跨膜离子通道功能）。 本4年提案的具体目标是完成 表征unc-1基因，表征导致突变的类型 以改变对挥发性麻醉剂的敏感性，并寻找 作为UNC-1的抑制剂。 这些具体目标的最终目标是 在一个模型系统中使用分子遗传学来了解 麻醉药的作用，合理设计改进的麻醉药 知识，并使用麻醉部位和作用机制的知识 作为分析意识本质的一种探索。

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.