Michael Crowder, MD, PhD
Dr. Seymour and Rose T Brown Professor of Anesthesiology
Fundamental mechanisms of neuronal cell death following hypoxic injury Read More
|Lab Phone:||(314) 747-0669|
|Lab Location:||Clinical Sciences Research Building 5536|
|Keywords:||hypoxic injury, ischemic injury, neuronal cell death, protein folding homeostasis, C. elegans genetics, behavioral assays, cell death assays, transgenic animal generation, mutant identification, RNAi techniques, mouse primary neuronal cultures|
Fundamental mechanisms of neuronal cell death following hypoxic injury
We are using 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 genetically tractable 1 mm-long non-parasitic nematode with a well-characterized nervous system and completely sequenced genome. Through mutant screens, we have uncoverd genes encoding presynaptic proteins that markedly alter the sensitivity of C. elegans to general anesthetics. Through molecular, genetic, and biochemical approaches, we are defining how these presynaptic proteins regulate anesthetic action in C. elegans and potentially in humans.
Hypoxic cell death in the form of heart attacts and strokes is the number one killer in this country. C. elegans genetics has made seminal contributions for apoptotic cell death yet has been little studied for hypoxic death. Via a variety of genetic approaches, we have found several pathways that regulate hypoxic sensitivity and/or adaptation to hypoxic. These pathways include those that regulate insulin/IGF receptor signaling, those mediating Ca++-induced necrotic cell death, and the apoptosis pathway. We are currently genetically mapping new hypoxia-resistant mutants, performing RNAi-based screens, and analyzing DNA microarray studies to identify additional regulators of hypoxic sensitivity. The ultimate goals of these experiments are to gain a thorough understanding of the entire complement of killer, protector, and adaptive genes controlling hypoxic injury and death. Methods in the lab are primarily behavioral genetics, genomics, and molecular biology.
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