The Neurobiology of Hypoxia Tolerance in the Naked Mole-Rat

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This project will contribute to understanding tolerance of hypoxia (low oxygen levels) within the nervous system by studying the African naked mole-rat. This mammal lives in crowded, oxygen-starved burrows, and has evolved the ability to survive extended periods of oxygen deprivation without triggering brain cell death. This project will test new target genes that may protect brain cells from cell death resulting from exposure to hypoxia, with potential applications in designing new treatments for humans that experience oxygen deprivation during traumatic events like a stroke or heart attack. By studying the genome of the naked mole-rat, the investigators previously discovered changes in the genes of this species that likely reduce cell death from oxygen deprivation. The goal of the current project is to test each of those genes for its potential role in brain cell protection. The project will support two graduate students each year, who will help mentor a number of undergraduate student researchers recruited from existing programs targeting students from groups underrepresented in science. Information on the naked mole-rat will be shared via outreach to a local zoo and area high schools. This project will investigate molecular, cellular, and physiological mechanisms in the brain that underly hypoxia tolerance and will contribute to understanding evolutionary adaptations to environmental challenges in general. The naked mole-rat will be developed as a model system for studying the molecular and genetic basis of hypoxia tolerance in the mammalian brain. Brain cells from the naked mole-rat display an intrinsic tolerance to hypoxia and a dramatic reduction in calcium accumulation during hypoxia compared with most other mammals, which is hypothesized to result from multiple adaptations that limit and buffer calcium currents. Additionally, there appears to be a significant neuroprotective role for the endocannabinoid system in the brain of the naked mole-rat. This project will specifically examine the neuroprotective function of the calcium channel TRPM7, NMDA glutamate-receptor ion channels, a calcium-related kinase, and the calcium-binding protein parvalbumin, as well as the endocannabinoid system. The investigators will use brain slice electrophysiology, mass spectrometry, and gene manipulation techniques to determine the molecular and genetic basis of hypoxia tolerance in the naked mole-rat. Experiments designed to introduce naked mole-rat-specific gene alterations into mouse cells will test the hypothesis that the changes in the naked mole-rat genes can also protect other species. Understanding how brain cells are protected from oxygen deprivation may ultimately lead to new therapeutic targets for heart attack and stroke victims. Several graduate and undergraduate student trainees will participate in the research, and results will be incorporated into undergraduate courses and outreach activities.This award was co-funded by the Physiological Mechanisms and Biomechanics Program and the Neural Systems Cluster Organization Program in BIO-IOS.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.