MOLECULAR PHARMACOLOGY OF ANESTHETICS IN C ELEGANS

这项研究的长期目标是了解分子 挥发性麻醉药的作用基础。 很少有人知道如何 挥发性麻醉剂产生可逆的无意识;这是 无论是在大体解剖学上， 亚细胞/分子水平。 该提案使用分子 遗传学的方法，试图了解的作用机制， 秀丽隐杆线虫中的挥发性麻醉剂。 完全定义的 神经解剖学和广泛的遗传分析，使它成为一种 一个有吸引力的，简单的，模型系统。 另外我们有 发现了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 麻醉剂 它们的行为表明， 麻醉作用 这些突变菌株，unc-79和unc-80， 当与其他药物结合时， 突变，UNC-9或UNC-7。 我们计划利用这些突变 了解麻醉剂作用部位的分子性质。 这项建议的具体目标是： 1)为了表征麻醉反应的遗传控制， 通过分离另外的unc-79，unc-80，unc-100和unc-100的等位基因， 9和unc-7。 还将寻找新的突变， 对不同麻醉剂过敏或抵抗。 2)为了构建动物的基因嵌合体， 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。 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拯救来克隆unc-79。 我们计划分析相应的一级结构 蛋白质产品，并搜索同源蛋白质产品， 更复杂的有机体。 确定挥发性药物作用部位的组分 麻醉药是研究作用机制的第一步 这些代理人。 定义的分子作用机制 挥发性麻醉剂在一个相对简单的生物体，秀丽隐杆线虫， 可以确定生产的基本过程， 其他物种的无意识 这些知识可能至关重要 在将来合成挥发性麻醉剂的尝试中， 例如，现在在麻醉药品中出现特异性 疗法

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.