Mechanisms of metabolic rate depression: following Nature's way

我实验室的研究重点是生化适应，即让动物在严峻的环境挑战(如寒冷/冰冻温度、缺氧、脱水)中生存的机制，以及最极端的生存策略的统一特征-代谢率抑制(MRD)。利用哺乳动物冬眠、耐冻性和缺氧或脱水生存的分子工具和脊椎动物模型，我们探索应激反应代谢调节，以确定有助于生存的统一原则和独特的应激/机体特异性适应。基于过去六年收集的数据和测试的概念，未来的研究计划围绕四个关键领域具体化。(1)表观遗传学和基因表达：我们最近的工作提供了强有力的证据，表明影响DNA和组蛋白的表观遗传学机制(乙酰化、甲基化)是MRD重建新陈代谢以求生存的重要因素。继续的工作将扩大到评估不同的应激/动物系统，以确认表观遗传控制作为MRD和应激抵抗的原则。针对冬眠者的重点研究还将探索其他甲基化控制措施(mRNA的腺苷甲基化和蛋白质的精氨酸甲基化)，作为外周时钟蛋白的假定调节器，当中央下丘脑时钟停止功能时，这些蛋白可能维持器官间的燃料代谢。(2)microRNA：在我们对microRNA在低代谢过程中调节mRNA翻译快速变化的差异microRNA表达进行广泛分析的基础上，下一步的研究将集中在两个新途径上：调节miRNA生物发生机制以支持miRNA对应激的反应，以及释放到血液中的miRNAs参与组织间的沟通，潜在地增强应激/MRD条件下代谢需求的协调。(3)转录因子：对环境胁迫的适应主要是通过蛋白质的作用实现的，而蛋白质又通过转录因子(TF)被诱导或上调/下调。展望未来，我们将重点关注四个TF家族(OCT、Mondoa、SREBP和HNF)，它们分别在介导抗氧化防御、葡萄糖诱导作用、脂质代谢和凝血因子产生方面发挥重要的代谢作用。对于生活在低代谢状态的动物来说，这些都是至关重要的需求，但到目前为止，这些因子还没有得到分析。(4)酶适应：调节中间能量代谢的酶一直是我职业生涯的核心重点，特别强调通过可逆的蛋白质磷酸化来控制糖酵解和其他胞浆酶。基于对两种线粒体酶的新研究，拟议的研究将把重点转移到应激/MRD下的线粒体酶调节和潜在的线粒体特异性修饰(例如，戊二酸化)，这可能是关键的调节因素。总体而言，我们的建议将在我们对动物生化适应策略的知识方面取得新的进展。

Research in my lab focuses on biochemical adaptation, the mechanisms that allow animals to survive severe environmental challenges (e.g. cold/freezing temperatures, oxygen deprivation, dehydration) as well as the unifying feature of most extreme survival strategies - metabolic rate depression (MRD). Using molecular tools and vertebrate models of mammalian hibernation, freeze tolerance, and anoxia or dehydration survival, we explore stress-responsive metabolic regulation to identify unifying principles and unique stress/organism specific adaptations that contribute to survival. Building on data gathered and concepts tested over the last six years, research plans going forward have crystallized around four key areas. (1) EPIGENETICS & GENE EXPRESSION: Our recent work has produced strong evidence that epigenetic mechanisms (acetylation, methylation) affecting DNA & histones are significant contributors to MRD to resculpt metabolism for survival. Continuing work will expand to evaluate diverse stress/animal systems to confirm epigenetic controls as a principle of MRD and stress resistance. Focused research on hibernators will also explore other methylation controls (adenosine methylation of mRNA & arginine methylation of proteins), as putative regulators of peripheral clock proteins that may sustain inter-organ fuel metabolism when central hypothalamic clocks cease function. (2) MICRO-RNA: Building on our extensive analysis of differential microRNA expression in mediating rapid changes in mRNA translation during hypometabolism, next step studies will focus on two new avenues: regulation of the miRNA biogenesis machinery to support miRNA responses to stress, and the proposal that miRNAs released into the bloodstream are involved in tissue-to-tissue communication potentially enhancing coordination of metabolic needs under stress/MRD conditions. (3) TRANSCRIPTION FACTORS: Adaptation to environmental stress is primarily implemented by the actions of proteins that are, in turn, induced or up/down regulated via transcription factors (TFs). Going forward, we are focusing of four TF families (OCT, MondoA, SREBP, HNF) that have important metabolic roles in mediating antioxidant defenses, glucose-induced actions, lipid metabolism, and clotting factor production, respectively. These are all crucial needs for animals living in hypometabolic states but these TFs have eluded analysis to date. (4) ENZYME ADAPTATION: The regulation of enzymes of intermediary energy metabolism has been a core focus of my career, with a particular emphasis on control of glycolytic & other cytosolic enzymes by reversible protein phosphorylation. Based on new studies of two mitochondrial enzymes, proposed research will shift focus to mito-enzyme regulation under stress/MRD and potential mito-specific modifications (e.g. glutarylation) that may be key regulators. Overall, our proposals will make novel advances in our knowledge of animal strategies of biochemical adaptation.