We study the genetic basis of physiological resilience, specifically how genes control life processes in dormancy and homeostatic responses to extreme physical chemical conditions.

Low temperature (hypothermia) and reduced oxygen (hypoxia) pervasively affect cellular metabolism and physiology, modulate organismic ageing, and trigger instinctive animal behaviors. Many species in nature have evolved unique traits to respond and adapt to severe hypothermia/hypoxia by maintaining homeostatsis or entering dormancy. The nematode C. elegans can be frozen alive, suspend life and revive later virtually any long after freezing, unlike many other common multicellular organisms. In humans, tissue injuries caused by ischemia-reperfusion can be alleviated by therapeutic hypothermia, now used in clinics for patients with ischemic disorders, including stroke and heart attack. Mechanisms of therapeutic hypothermia and the genetic basis underlying innate hypoxia/hypothermia/freezing tolerance in multicellular organisms remain largely unknown.

We use 1) genetically tractable C. elegans mutants isolated from large-scale screens with abnormal behavioral and extremophile-like phenotypes and 2) Mangrove Killifish, the only known self-fertilizing vertebrate with genetics similar to that of C. elegans and known extreme phenotypes, as discovery tools. We also culture neural stem cells from hibernating ground squirrels to understand cellular intrinsic tolerance of hypoxia/hypothermia. Genes identified from these systems via unbiased screens encode proteins of unusual properties that define novel mechanisms underlying cytoprotection, cellular organelle dynamics and organismic homeostasis in physiology and behaviors. New findings from our research may foster novel means of cytoprotection, organ transplantation, reversible cryo-preservation and therapeutics to treat metabolic, neurological and ischemic disorders.

We are grateful for current funding support from NIH/NIGMS (R01 and R35 MIRA awards), Pew Charitable Trusts (Pew scholar award) and the David and Lucile Packard Foundation (fellowship award), as well as past support from NIH (K99 award), American Heart Association, the Larry L. Hillblom Foundation, American Diabetes Association, Alfred P. Sloan Foundation, Esther A. & Joseph Klingenstein Fund and the Shurl & Kay Curci Foundation (SKCF) Faculty Scholars program.