Grant: Discovery Grants Program - Individual

Research in my lab focuses on biochemical adaptation, the mechanisms that allow animals to survive severe environmental challenges (e.g. cold/freezing temperatures, oxygen deprivation, dehydration) as well as the unifying feature of most extreme survival strategies - metabolic rate depression (MRD). Using molecular tools and vertebrate models of mammalian hibernation, freeze tolerance, and anoxia or dehydration survival, we explore stress-responsive metabolic regulation to identify unifying principles and unique stress/organism specific adaptations that contribute to survival. Building on data gathered and concepts tested over the last six years, research plans going forward have crystallized around four key areas. (1) EPIGENETICS & GENE EXPRESSION: Our recent work has produced strong evidence that epigenetic mechanisms (acetylation, methylation) affecting DNA & histones are significant contributors to MRD to resculpt metabolism for survival. Continuing work will expand to evaluate diverse stress/animal systems to confirm epigenetic controls as a principle of MRD and stress resistance. Focused research on hibernators will also explore other methylation controls (adenosine methylation of mRNA & arginine methylation of proteins), as putative regulators of peripheral clock proteins that may sustain inter-organ fuel metabolism when central hypothalamic clocks cease function. (2) MICRO-RNA: Building on our extensive analysis of differential microRNA expression in mediating rapid changes in mRNA translation during hypometabolism, next step studies will focus on two new avenues: regulation of the miRNA biogenesis machinery to support miRNA responses to stress, and the proposal that miRNAs released into the bloodstream are involved in tissue-to-tissue communication potentially enhancing coordination of metabolic needs under stress/MRD conditions. (3) TRANSCRIPTION FACTORS: Adaptation to environmental stress is primarily implemented by the actions of proteins that are, in turn, induced or up/down regulated via transcription factors (TFs). Going forward, we are focusing of four TF families (OCT, MondoA, SREBP, HNF) that have important metabolic roles in mediating antioxidant defenses, glucose-induced actions, lipid metabolism, and clotting factor production, respectively. These are all crucial needs for animals living in hypometabolic states but these TFs have eluded analysis to date. (4) ENZYME ADAPTATION: The regulation of enzymes of intermediary energy metabolism has been a core focus of my career, with a particular emphasis on control of glycolytic & other cytosolic enzymes by reversible protein phosphorylation. Based on new studies of two mitochondrial enzymes, proposed research will shift focus to mito-enzyme regulation under stress/MRD and potential mito-specific modifications (e.g. glutarylation) that may be key regulators. Overall, our proposals will make novel advances in our knowledge of animal strategies of biochemical adaptation.