C. Michael Crowder, MD, PhD
Alan J. Treuer Endowed Professor of Anesthesiology and Pain Medicine
Chairman Department of Anesthesiology and Pain Medicine
Adjunct Professor of Genome Sciences
Hypoxia and reoxygenation create havoc in cells. This havoc if unrepaired will ultimately lead to cell dysfunction and death in diseases such as myocardial infarction and stroke, the number one causes of death and disability in the US. Unfortunately, no effective therapy for hypoxic injury, short of restoring oxygenation, has been approved, suggesting that an unrecognized aspect of hypoxic injury is not being effectively treated by previous strategies. With this in mind, my lab has taken a relatively underutilized approach of performing forward genetic screens in the nematode C. elegans to discover novel mechanisms of hypoxic injury and protection. In our forward screens, the largest and most effective class of hypoxia resistant mutants and RNAis are those that mitigate protein misfolding stress. We have recently discovered that hypoxia produces protein misfolding, not only in the cytoplasm and endoplasmic reticulum, but also in the mitochondria. My lab currently has active projects exploring the role of cell non-autonomous mechanisms of hypoxic injury, identification of new genes controlling hypoxic injury, defining the mechanisms and role of mitochondrial protein misfolding in hypoxic injury and ageing, and discovering new drugs that protect from hypoxic via high throughput screens.
- Sun C-L, Zhang H, Liu M, Wang W, Crowder CM (2017) A screen for protective drugs against delayed hypoxic injury. PLoS ONE 12(4): e0176061.
- Mao XR, Kaufman, and Crowder CM. Nicotinamide mononucleotide adenylyltransferase promotes hypoxic survival by activating the mitochondrial unfolded protein response, Cell Death and Disease 7:e2113, 2016
- Kaufman DM and Crowder CM. Mitochondrial proteostatic collapse leads to hypoxic injury, Current Biology 25(16):2171-76, 2015.
- Sun C-L, Kim E, Crowder CM. Delayed innocent bystander cell death following hypoxia in C. elegans. Cell Death and Differentiation 21(4):557-67, 2014.
- 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.
- Anderson LL, Mao X, Scott BA, Crowder CM. Survival from hypoxia by inactivation of aminoacyl-tRNA-Synthetases. Science 2009 323: 630-33.
- Mabon ME, Mao X, Jiao Y, Scott BA, Crowder CM. Systematic identification of gene activities promoting hypoxic death. Genetics 2009 181:483-96.