MOLECULAR PHARMACOLOGY OF ANESTHETICS IN C ELEGANS

这项研究的长期目标是了解分子 挥发性麻醉剂的作用基础。人们对此知之甚少 挥发性麻醉剂会产生可逆的无意识；这是 这是我们在大体解剖或 亚细胞/分子水平。这项提议使用了一种分子 用遗传学的方法试图了解黄连的作用机制 线虫中的挥发性麻醉剂。完全定义的 线虫的神经解剖学和广泛的遗传分析使其成为 一个吸引人的、简单的、模范的系统。此外，我们还有 鉴定出两个不协调的突变体，它们与 野生型蠕虫对最有效的挥发性物质的敏感性 麻醉剂。他们的行为表明 麻醉作用。这些突变株UNC-79和UNC-80可以 当它们与其他药物联合使用时，它们在麻醉剂中的表现正常 突变，UNC-9或UNC-7。我们计划利用这些突变来 了解麻醉作用部位的分子性质。 这项建议的具体目标是： 1)表征麻醉反应的遗传控制。 通过分离UNC-79、UNC-80、UNC-80的额外等位基因 9和UNC-7。还将寻求新的突变，以赋予 对不同的麻醉药过敏或耐药。 2)为北卡罗来纳大学构建具有遗传嵌合体的动物- 79或UNC-9或UNC-7，从而精确地确定每一种 这些基因与特定的细胞谱系或特定的组织有关。 3)利用转座子标签技术克隆UNC-79和UNC-80。 我们还将尝试通过突变体营救的方式克隆UNC-79。 我们计划分析相应的初级结构 蛋白质产品，并在 更复杂的有机体。 挥发性物质作用部位成分的测定 麻醉药是研究作用机制的第一步。 这些特工的名字。明确其作用的分子机制 一种相对简单的生物体中的挥发性麻醉剂，线虫， 可能会确定作为生产基础的非常基本的过程 其他物种的无意识。这样的知识可能是至关重要的 在未来合成挥发性麻醉剂的尝试中 例如，现在在麻醉剂中出现的特异性 心理治疗。

The long term goal of this study is to understand the molecular basis of action of volatile anesthetics. Little is known about how volatile anesthetics produce reversible unconsciousness; this is true of our understanding at either the gross anatomical or subcellular/molecular level. This proposal uses a molecular genetic approach to try to understand the mechanism of action of volatile anesthetics in C.elegans. The completely defined neuroanatomy and extensive genetic analysis of C.elegans make it an attractive, simple, model system. In addition, we have identified two uncoordinated mutants that differ greatly from the wild type worm in their sensitivity to the most potent volatile anesthetics. Their behavior indicates a change at the site of anesthetic action. These mutant strains, unc-79 and unc-80, can each behave normally in anesthetics when combined with other mutations, unc-9 or unc-7. We plan to use these mutations to understand the molecular nature of the site of anesthetic action. The specific aims of this proposal are: 1) To characterize the genetic control of anesthetic response in C.elegans by isolating additional alleles of unc-79, unc-80, unc- 9 and unc-7. New mutations will also be sought that confer hypersensitivity or resistance to different anesthetics. 2) To construct animals that are genetic mosaics for either unc- 79 or unc-9 or unc-7, and thus pinpoint the effects of each of these genes to specific cell lineages, or to specific tissues. 3) To clone unc-79 and unc-80 by a transposon tagging technique. We will also attempt to clone unc-79 by means of mutant rescue. We plan to analyze the primary structure of the corresponding protein products, and search for homologous protein products in more complex organisms. Determining the components of the site of action of volatile anesthetics is the first step in studying the mechanism of action of these agents. Defining the molecular mechanism of action of volatile anesthetics in a relatively simple organism, C.elegans, may identify very basic processes that underlie the production of unconsciousness in other species. Such knowledge may be crucial in future attempts to synthesize volatile anesthetic agents with the specificity now seen, for example, emerging in narcotic therapy.