Frontiers in Anesthesia Research Award
C. Michael Crowder, MD, PhD
Cellular and Molecular Mechanisms of Hypoxic and Anesthetic Preconditioning
2009 FARA
Washington University
in
St. Louis
Dr. Seymour and Rose T. Brown Professor, Anesthesiology
Director, Division of Basic Research, Anesthesiology
Associate Professor,
Developmental Biology
Research Interests and Activities
Hypoxia, the insufficient supply of oxygen to cells, ultimately results in cell death and is commonly the cause of heart attacks and strokes. Additionally, resistance to hypoxic cell death is a significant contributor to cancer cell metastasis and tumor growth. Dr. Crowder and his team are working to develop an understanding of hypoxic cellular injury to facilitate the development of novel therapeutics for hypoxic cell death. Successful completion of his study could result in new treatments for heart attack, stroke and cancer.
Through screens in a soil nematode, Caenorhabditis elegans (C. elegans), the Crowder Lab has found that proteostasis genes are critical to hypoxic survival. In response, they are testing the hypoxic survival of mouse neurons, using the genetic tools of C. elegans to define the mechanisms by which these genes control survival after hypoxic injury.
-
What methods and techniques are you using in your study?
We have identified transcription factors that respond to hypoxic injury and are now searching for the genes that are regulated by these factors using whole-genome microarrays. We are also using viral vectors to test the mouse versions of the C. elegans genes in a cell culture model of hypoxic injury.
-
What research advances have been permitted by your IARS grant?
At the time of submission of the IARS grant, we had proposed that hypoxia-induced protein misfolding might promote cell death and adaptation depending on the hypoxic severity. The IARS grant has allowed us to test these hypotheses and have thereby discovered that a specific branch of the unfolded protein response is essential for hypoxic preconditioning. This is an entirely novel finding and has important implications for survival from hypoxic injury.
-
Is there potential for subsequent studies following the completion of your investigation?
We are now looking for the mechanism downstream of the unfolded protein response pathway that control hypoxic death and adaptation. Defining these pathways is important for understanding the biology of hypoxic injury and should form the basis for a fruitful series of investigations.
-
In your opinion, how does anesthesia research impact patient care and the specialty?
While anesthesiologists have made numerous discoveries that have increased the safety of surgery and anesthesia, there is still a great deal of perioperative morbidity and mortality. Anesthesia-related research offers the possibility for our specialty to continue to make important fundamental contributions to the field of medicine.
Selected Publications
Mao XR, Crowder CM. Protein misfolding induces hypoxic preconditioning via a subset of the unfolded protein response machinery. Mol Cell Biol 30(21):5033-42, 2010.
Crowder CM. Ceramides – Friend or Foe in Hypoxia? Science 324:343-344, 2009.
Anderson LL, Mao X, Scott BA, Crowder CM. Survival from hypoxia in C. elegans by inactivation of aminoacyl-tRNA-Synthetases. Science 323: 630-33, 2009
Mabon ME, Mao X, Jiao Y, Scott BA, Crowder CM. Systematic identification of gene activities promoting hypoxic death. Genetics 181(2):483-96, 2009.