|Office:||Office: 507 Steacie Building|
Lab: 503, 505, 424, 431, 438 Steacie Building
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Themes: Metabolic regulation, biochemical adaptation, gene expression, dormancy, hibernation, cryobiology, living without oxygen.
Model systems: Hibernation (ground squirrels, bats), freeze tolerance (frogs, turtles, snails, insects), estivation (snails, frogs, toads), anoxia survival (turtles, snails, crayfish)
Research tools: Enzymology, signal transduction studies, protein purification & structure, RT-PCR, cDNA arrays, RACE, EMSA, protein expression, immunoblotting
Major research directions:
A. Metabolic Rate Depression – An impressive array of organisms can radically suppress their basal metabolic rate and enter a hypometabolic state (torpor, dormancy) characterized by the suspension of normal physiological functions. Metabolic rate depression, often lowering metabolism to just 5-20% of normal, is typically used to elude harsh environmental conditions such as low oxygen, low temperature, or lack of water. We have demonstrated a common basis for the regulation of hypometabolism across phylogeny using model systems of mammalian hibernation (ground squirrels, bats), estivation (land snails, spadefoot toads, African clawed frogs), and anoxia tolerance (freshwater turtles & crayfish, marine snails). We have found multiple mechanisms that contribute to metabolic rate depression including: 1) Reversible phosphorylation of key regulatory enzymes and functional proteins (e.g. glycolytic enzymes, Na+K+-ATPase, ribosomal initiation factors) to produce less active enzyme forms, and 2) Differential up-regulation of selected genes during entry into or arousal from a hypometabolic state to produce proteins that regulate and stabilize hypometabolism. New studies are moving in two directions. Studies of signal transduction are analyzing the second messengers, protein kinases and phosphatases, and transcription factors that are responsible for initiating and coordinating metabolic arrest. Studies of gene expression are analyzing the patterns and influences on gene expression, global methods of gene silencing during dormancy including epigenetic mechanisms, and investigating the actions/roles of novel gene products. This research has potential medical applications for extending the preservation times of organs that are removed for transplant or developing methods for inducible dormancy in humans.
B. Freeze Tolerance – Although alien to man, winter survival for many animals includes the ability to endure the freezing of extracellular body fluids. We study several Canadian species as models including wood frogs, painted turtles, goldenrod gall insects and intertidal marine snails. Adaptations that we have identified as supporting freeze tolerance include: 1) Proteins: nucleating proteins induce and regulate extracellular freezing; thermal hysteresis proteins prevent recrystallization, 2) Cryoprotectants: high concentrations of polyols and sugars prevent excessive cell volume reduction, increase intracellular bound water content, and stabilize proteins and membranes, and 3) Ischemia tolerance: blood freezing requires organs to survive without oxygen and nutrient delivery for long periods of time whereas good antioxidant defenses are used to resist oxidative stress when oxygen is suddenly reintroduced upon thawing. Our studies with freeze tolerant frogs and turtles are targeting a variety of questions that we hope will lead to applied solutions that can be used to improve the cryopreservation of transplantable human organs. New work includes a major focus on the role of gene expression in freezing survival including the identification of novel genes and their protein products that have never before been implicated in freeze endurance. Other studies are analyzing the roles of protein kinases and protein phosphatases in coordinating the metabolic changes that occur during freezing and determining how frog cells can endure the extremely high levels of glucose that are accumulated as a cryoprotectant, levels that would be lethal to human diabetics.