Sandy Martin, Professor at the University of Colorado School of Medicine
University of Colorado Anschutz Medical Campus
sandy.martin@cuanschutz.edu
The goal of our research is to discover the relationship between genome and phenome that underlies the remarkable physiology of hibernation. Hibernators have naturally solved many of the intractable problems that plague human medicine; we believe that decoding these solutions offers unparalleled opportunity to design new approaches that will mitigate and reverse damage from cardiac arrest, stroke, trauma, obesity, and from bone and muscle disuse atrophy. Our model organism is the thirteen-lined ground squirrel, which hibernates for about half the year. During hibernation, these remarkable mammals cycle their physiology between two extremes, torpor and arousal, with the vast majority of the time spent in torpor. To enter torpor, metabolic rate is dropped to just 5% of basal in concert with severe depression of heart and respiratory rates. Core body temperature then plummets to near freezing, further enhancing and stabilizing the metabolic depression; this extreme physiology persists for ~two weeks and then is reversed rapidly and spontaneously, bringing core temperature and metabolism back to more typical mammalian homeostatic values where they remain for about 12 hours before the animal cycles back into torpor. The process of arousing from torpor and rewarming the body more than 30◦C takes just two hours, uses only endogenous mechanisms to generate heat (first non-shivering, then shivering thermogenesis), and occurs via an internal timing mechanism without environmental warming. In sharp contrast to hibernation, during the remainder of the year these animals maintain high metabolism and body temperature continuously and do not enter torpor. Annually and prior to the onset of winter, the animals also become obese. They suddenly stop eating, and switch to burning rather than storing fat, relying on this stored fuel throughout the six months of winter hibernation. The seasonal changes that distinguish the hibernation and active phases of their annual cycle include enhanced tissue protection in organs throughout the body during winter, and transient (notably, reversible) obesity. In torpor-arousal cycles, largely unknown mechanisms protect against ischemia-reperfusion damage despite intense metabolic activation during the short, rapid rewarming phase. To gain insight into the genetic and biochemical mechanisms underlying this remarkable physiology we have exploited the key feature of timing in both the seasonal cycle and the torpor-arousal cycle by collecting a tissue bank from ~ 200 precisely- timed animals in different stages of both cycles. The bank has provided robust information about protein and metabolite changes in sync with hibernation physiology, but we have just begun to scratch the surface of what this unique resource can reveal about this extraordinary phenotype. Ongoing efforts are directed towards understanding mechanisms of neuroprotection as well as metabolic control and body weight homeostasis using RNA-seq and other modern genomics methodologies.
