Dr. Crowder proposes to identify and characterize genes that control volatile anesthetic action in the nematode Caenorhabditis elegans in the hope that such findings will eventually be useful in the design of better anesthetics and in defining mechanisms responsible for anesthetic-induced nervous system depression. In preliminary studies, recombinant inbred strains of C. elegans have been found variant in their sensitivity to halothane, with halothane EC50 concentrations of 0.2 - 0.9 percent atm being in the same range of concentrations administered during surgical anesthesia. Genetic mapping of the halothane sensitivity phenotype in these recombinant inbred strains has identified 5 genetic loci that influence halothane potency. Dr. Crowder proposes to 1) continue identifying and mapping in recombinant inbred strains the loci that control volatile anesthetic action in C. elegans, which are presumed to code for targets or modulators of anesthetic action; 2) map individual loci in congenic strains, which allow determination of the independent effect of each locus on anesthetic sensitivity; 3) positionally clone the strongest loci controlling anesthetic sensitivity in C. elegans, which involves injecting the cloned DNA of the locus associated with anesthetic sensitivity into the gonad of an anesthetic-resistant animal and screening the progeny for the anesthetic-sensitive phenotype; 4) analyze the sequence of genes that control anesthetic sensitivity; and 5) characterize the expression of cloned genes, including RNA expression and the distribution of the actual gene product. It is hoped that these results will help guide in vitro and in vivo studies in higher organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM055832-01
Application #
2024383
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1997-05-01
Project End
2001-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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van Swinderen, Bruno; Metz, Laura B; Shebester, Laynie D et al. (2002) A Caenorhabditis elegans pheromone antagonizes volatile anesthetic action through a go-coupled pathway. Genetics 161:109-19
van Swinderen, B; Metz, L B; Shebester, L D et al. (2001) Goalpha regulates volatile anesthetic action in Caenorhabditis elegans. Genetics 158:643-55
van Swinderen, B; Galifianakis, A; Crowder, C M (1998) A quantitative genetic approach towards volatile anesthetic mechanisms in C. elegans. Toxicol Lett 100-101:309-17
van Swinderen, B; Galifianakis, A; Crowder, M (1998) Common genetic determinants of halothane and isoflurane potencies in Caenorhabditis elegans. Anesthesiology 89:1509-17