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.
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