Associate Professor
Anesthesiology
Developmental Biology
Email Website Contact Info More Publications
We are using the powerful genetically trac model, the nematode Caenorhabditis elegans, to address two distinct questions: 1) What are the molecular mechanisms whereby general anesthetics disrupt nervous system function? 2) What are the genetic determinants of hypoxic cell death? C. elegans is a small non-parasitic worm with a well-characterized nervous system that directs a number of complex behaviors. We have identified single gene mutations and quantitative trait loci that markedly alter the sensitivity of C. elegans to volatile anesthetics. In particular, mutations in a number of presynaptic proteins render C. elegans either resistant or hypersensitive to anesthetics. Through primarily genetic and biochemical approaches, we are defining how these gene products regulate anesthetic action. In the end, we should know what are the molecular targets of general anesthetics in C. elegans, and, perhaps, those operant in the vertebrate nervous system. Our work on hypoxic death is motivated by the fact that stroke and heart attack, a result of hypoxic cell death, are together the number one cause of human death in the US. C. elegans genetics has made seminal contributions for apoptotic cell death yet is relatively untapped for hypoxic death. We have found several mutant strains that are hypoxia resistant. The mutant genes thusfar identified fall into two categories: those that diminish insulin/IGF receptor signaling and those that diminish Ca++-mediated necrotic cell death. The insulin receptor mutants produce profound protection from hypoxia through a PIP3-kinase cascade leading to phosphorylation of a forkhead-type transcription factor. The hypoxic protection provided by the Ca++-mediated necrotic cell death mutants suggest that the mechanisms of hypoxic cell death in vertebrates and C. elegans overlap since divalent cations have been implicated in hypoxic death of vertebrate neurons.
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Research Publications
Hawasli AH, Saifee O, Liu C, Nonet ML, Crowder CM (2004 Oct). Resistance to volatile anesthetics by mutations enhancing excitatory neurotransmitter release in Caenorhabditis elegans. Genetics. 168 (2): 831-43. Full Article >
Nagele P, Metz LB, Crowder CM (2004 Jun 8). Nitrous oxide (N(2)O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 101 (23): 8791-6. Full Article >
Scott BA, Avidan MS, Crowder CM (2002 Jun 28). Regulation of hypoxic death in C. elegans by the insulin/IGF receptor homolog DAF-2. Science. 296 (5577): 2388-91. Full Article >
van Swinderen B, Metz LB, Shebester LD, Crowder CM (2002 May). A Caenorhabditis elegans pheromone antagonizes volatile anesthetic action through a go-coupled pathway. Genetics. 161 (1): 109-19. Full Article >
van Swinderen B, Metz LB, Shebester LD, Mendel JE, Sternberg PW, Crowder CM (2001 Jun). Goalpha regulates volatile anesthetic action in Caenorhabditis elegans. Genetics. 158 (2): 643-55. Full Article >
van Swinderen B, Saifee O, Shebester L, Roberson R, Nonet ML, Crowder CM (1999 Mar 2). A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 96 (5): 2479-84. Full Article >
Contact Info
Michael Crowder, M.D., Ph.D.
Office Location: 5536 Clinical Sciences Bldg.
Office Phone: 314-747-0669
Campus Box: 8054
Fax: 314-362- 8571
crowderm@morpheus.wustl.edu
http://elysium.wustl.edu/mclab/
