2009 Frontiers in Anesthesia Research Award $500,000
C. Michael Crowder, MD, PhD
During Award Period
Washington University in St. Louis
Dr. Seymour and Rose T. Brown Professor, Anesthesiology
Director, Division of Basic Research, Anesthesiology
Associate Professor, Developmental Biology
University of Washington School of Medicine
Chair, Department of Anesthesiology and Pain Medicine
Alan J. Treuer Endowed Professorship, Anesthesiology
Dr. Crowder’s Research
Cellular and Molecular Mechanisms of Hypoxic and Anesthetic Preconditioning
Research Description of The Crowder Lab at University of Washington
The Crowder Lab is interested in the genetic determinants of cellular injury after environmental stress, focused on two cell stresses, hypoxia and general anesthetics. The number one cause of mortality in the United States is heart attacks and strokes due to cell death after hypoxia. Dr. Crowder and his team are currently using genetic, cell biological, and biochemical methods to define the role and mechanisms of protein homeostasis and an insulin-like growth factor in hypoxic injury and have found that general anesthetics also disrupt protein homeostasis and that this contributes to significant behavioral deficits in C. elegans. As for hypoxic injury, the Crowder Lab is defining the factors that control general anesthetic effects on protein homeostasis.
Research Interests and Activities under the Frontiers Award
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 were working to develop an understanding of hypoxic cellular injury to facilitate the development of novel therapeutics for hypoxic cell death. Outcomes from his study could result in new treatments for heart attack, stroke, and cancer.
Working within a soil nematode, Caenorhabditis elegans (C. elegans), the Crowder Lab at Washington University found that proteostasis genes are critical to hypoxic survival. In response, they were 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.
Interview with Dr. Crowder
- 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.
Other Grants and Awards
Delayed innocent bystander cell death following hypoxia in Caenorhabditis elegans.
Sun CL, Kim E, Crowder CM.
After hypoxia, cells may die immediately or have a protracted course, living or dying depending on an incompletely understood set of cell autonomous and nonautonomous factors. In stroke, for example, some neurons are thought to die from direct hypoxic injury…
Role of oxygen consumption in hypoxia protection by translation factor depletion.
Scott B, Sun CL, Mao X, Yu C, Vohra BP, Milbrandt J, Crowder CM.
The reduction of protein synthesis has been associated with resistance to hypoxic cell death. Which components of the translation machinery control hypoxic sensitivity and the precise mechanism has not been systematically investigated, although a reduction in oxygen consumption has been widely assumed to be the mechanism. Using genetic reagents in Caenorhabditis elegans…
Read Dr. Crowder’s recent publications and articles.