Genetic pathway and cellular mechanism underlying organismic responses to hypoxia and hypothermia

Project Summary/Abstract Proper temperature and oxygen levels enable essential life activities. Low temperature (hypothermia) and reduced level of oxygen (hypoxia) pervasively influence fundamental biochemical processes, cellular metabolism, organismal physiology and behaviors. Hypoxia and oxidative stresses are also key features in

ischemic disorders, including stroke and heart attack, treatment of which can greatly benefit from the emerging procedure of “therapeutic hypothermia.” Our laboratory is interested in fundamental genetic analysis and mechanistic studies of hypoxia, hypothermia, innate ischemic tolerance in resilient organisms, and

cytoprotection against tissue injuries caused by metabolic stresses. We leverage genetically tractable C. elegans mutants isolated from large-scale screens with abnormal cell physiological and organismal behavioral phenotypes to discover novel mechanisms of stress resilience. In addition, we culture mammalian neural stem

cells isolated from hibernating ground squirrels to unravel cellular intrinsic mechanisms of hypoxia/hypothermia tolerance. With multidisciplinary approaches and technologies, we have been running a productive research program and already discovered novel mechanisms of action of genes, protein variants and pathways in

conferring cytoprotection and organismal responses to hypoxia and hypothermia. In this R35 application, we propose to continue these tractable and innovative lines of inquiries to expand our basic understanding of how cells and organisms cope with hypoxia and hypothermia, to characterize novel genes and pathways already

identified from our forward genetic and RNAi screens, and to identify key genetic determinants of innate hypoxia/ischemic tolerance in resilient organisms. The PI and laboratory’s extensive prior experience and expertise in diverse but complementary model systems are well suited for executing and successfully

completing the project in the Cardiovascular Research Institute at the University of California, San Francisco.