Molecular Adaptations of Mammalian Hypoxia Tolerance: Regulation of Oxidative Damage, Neuroprotection, and MicroRNA

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  • Prolonged exposure to limited oxygen can be lethal. Investigating the biological consequences of oxygen-deprivation in a hypoxia tolerant mammalian model can provide us with novel insights that could be applied to alleviate the ischemic insults experienced during stroke, or to better tolerate the hypoxia of high-altitude. Naked mole-rats (Heterocephalus glaber) represent nature's solution to the problem of both acute and chronic oxygen limitation among mammals, solutions that have developed over evolutionary time. In this thesis I investigate their unique adaptations. The data I collected paints a picture of intricate signalling mechanisms in place to facilitate metabolic reorganization and protection during hypoxia. I determine that naked mole-rats are not as vulnerable to hypoxia-induced oxidative damage, as compared to hypoxia intolerant animals, and that brains appear to be the most resilient. The cell-survival proteins I profile implicate the induction of mechanisms responsible for conserving energy and maintaining neural integrity under low oxygen levels. Next, I perform the first microRNA-sequencing analysis in naked mole-rats, focusing on the hypoxic brain. Hypoxia-induced microRNAs suppress ATP-expensive processes, activate central signalling pathways, and coordinate a shift to non-fructose based anaerobic glycolysis. I then examine global metabolic reorganization and characterize a microRNA-mediated, AMPK-driven shift to carbohydrate metabolism in hypoxic skeletal muscles that may support tissue-specific prioritization of energy for more essential organs. Taken together, these findings advance our understanding of mammalian hypoxia tolerance and highlight the molecular mechanisms and complex layered regulatory controls required to endure frequent hypoxia exposures, as well as provide directions for future studies.

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  • Copyright © 2021 the author(s). Theses may be used for non-commercial research, educational, or related academic purposes only. Such uses include personal study, research, scholarship, and teaching. Theses may only be shared by linking to Carleton University Institutional Repository and no part may be used without proper attribution to the author. No part may be used for commercial purposes directly or indirectly via a for-profit platform; no adaptation or derivative works are permitted without consent from the copyright owner.
Date Created
  • 2021


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