Mike CrowderSchool of Medicine, Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA F1000 Faculty Member (since 11 November 2005)
Dr Seymour and Rose T Brown Endowed Professor of Anesthesiology
We are using the powerful genetics of the nematode Caenorhabditis elegans to address to 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. Through both classical and quantitative genetic techniques, 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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