Evolutionary Mechanisms of Enhanced Environmental Stress Resistance - PROJECT SUMMARY Cellular responses to environmental stressors (e.g., hypoxia, metals, and oxidants) are essential to animal performance and their dysregulation is associated with blindness, cancer, and aging. These responses are mediated by protein-level mechanisms regulating cytoprotective programs essential to animal survival. However, the majority of our knowledge into these proteins stems from human and mouse systems, ignoring the rich diversity of animal specialists —such as fishes, whales, and birds—that have evolved to survive chronic hypoxia and oxidative stress. This limits our understanding of the organismal stress response, as well as our ability to modulate these pathways in novel and unanticipated ways. With hundreds of these animals now represented by high-quality genomes, my goal is to harness evolutionary adaptation to identify novel molecular mechanisms modulating the environmental stress response. I recently demonstrated the enhanced NRF2 stress response of birds, pinpointing the protein-level mechanisms responsible. Since then, I have produced strong preliminary data identifying additional novel mechanisms in avian NRF2, as well as equine NRF2 and HIF-1 stress responses—species adapted to environmental oxidants, metals and chronic hypoxemia. We have identified substantial overlap of these adaptive mechanisms with those implicated in human diseases, suggesting these animals have evolved additional compensatory mechanisms. My vision is to reverse engineer these animal systems to reveal novel strategies capable of modulating the NRF2 and HIF-1 axis in human diseases where they are dysregulated. Thus, my plan over the next five years is to dissect these systems with a range of interdisciplinary techniques. Through a research strategy that integrates diverse perspectives from evolutionary biology, biochemistry, and cell biology, my program will address major gaps in our understanding of how stress response pathways operate in natural systems. Thus, my work is well-poised to improve our understanding of human health by harnessing the molecular strategies ‘discovered’ by natural selection millions of years ago.
