Investigating The Mechanism of Arctic Ground Squirrel Hibernation and Adaptation to Extreme Environments for Finding Novel Chronic Disease Therapeutics - PROJECT SUMMARY The goal of this project is to understand the cellular and molecular mechanisms underlying natural metabolic resilience by studying Arctic ground squirrels, animals that have evolved extraordinary physiological adaptations in the arctic that are directly relevant to major human health challenges. In this proposal we want to establish tools that will allow us to develop arctic ground squirrels as a model system to study the phenomenal metabolic plasticity. This approach marks a shift from traditional disease research, which focuses on pathological states in laboratory animals, toward investigating evolutionary mechanisms that allow animals to survive in the arctic. Current biomedical research often relies on inducing disease states in model organisms to study diseases states. While this approach has yielded important insights in many human diseases, it has not yielded desired results in many chronic human diseases like diabetes, muscle wasting, and ischemic injury. In contrast, millions of years of evolution have produced animals with natural resistance to conditions that cause severe pathology in humans. Arctic ground squirrels represent perhaps the most extreme example of metabolic resilience in mammals, yet these adaptations remain largely unexplored with modern molecular tools. They exhibit three extraordinary capabilities with direct therapeutic relevance. First, they naturally develop profound insulin resistance during pre- hibernation, gaining up to 65% of body weight—then completely reverse this without diabetes, cardiovascular disease, or other complications. This offers a natural model of reversible insulin resistance with transformative potential for diabetes therapy. Second, they maintain muscle mass and strength through 6–8 months of complete inactivity, addressing the critical challenge of muscle wasting in aging, disease, and therapeutic interventions. Third, hibernators resist ischemia-reperfusion injury, surviving global ischemic insults fatal to other mammals, offering insights into cardiovascular and neurological protection. This proposal will leverage cutting-edge tools to unlock these evolutionary solutions. We are developing the first iPSC lines from any Arctic species, enabling cellular models for mechanistic studies previously impossible in these difficult to access animals. We are also developing transgenic Arctic ground squirrels using modern reproduction biology tools. These genetic tools, combined with circuit neuroscience approaches—including tissue clearing, lightsheet microscopy, and single- cell genomics—will enable molecular dissection of physiological adaptions in these animals. The research integrates my experience spanning circuit neuroscience, biochemistry and field studies at Toolik Field Station in the Arctic, creating a pipeline that captures natural adaptations while enabling mechanistic investigation. By studying metabolic flexibility, tissue preservation, and cellular protection in Arctic ground squirrels, this work will identify novel therapeutic targets and strategies. This approach represents a paradigm shift toward studying natural resilience rather than artificial pathology, with potential to transform treatments for diabetes, muscle wasting, and ischemic disease.
