Mechanisms of metabolic rate depression: following Nature's way

代谢率降低的机制：遵循自然之道

• 批准号: RGPIN-2020-04733
• 负责人: Storey, Kenneth
• 金额: $ 5.68万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716097
• 关键词: Mechanisms; metabolic; rate; depression; following

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.

我实验室的研究重点是生物化学适应，使动物能够在严峻的环境挑战（例如寒冷/冰冻温度，缺氧，脱水）中生存的机制，以及大多数极端生存策略的统一特征代谢率抑制（MRD）。使用分子工具和哺乳动物冬眠，冷冻耐受性，缺氧或脱水生存的脊椎动物模型，我们探索应激反应的代谢调节，以确定统一的原则和独特的压力/生物体特异性适应，有助于生存。在过去六年收集的数据和测试的概念的基础上，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：我们最近的工作已经产生了强有力的证据，表明影响DNA和组蛋白的表观遗传机制（乙酰化，甲基化）是MRD的重要贡献者，以重新塑造代谢以生存。持续的工作将扩大到评估不同的压力/动物系统，以确认表观遗传控制作为MRD和抗压力的原则。对冬眠动物的重点研究还将探索其他甲基化控制（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剂，当中央下丘脑时钟停止功能时，可能会维持器官间的燃料代谢。 (2)微RNA：基于我们对差异microRNA表达在介导低代谢期间mRNA翻译快速变化方面的广泛分析，下一步研究将集中在两个新途径上：调节miRNA生物合成机制以支持miRNA对应激的反应，以及释放到血液中的miRNA参与组织间通讯的提议，这可能增强应激/MRD条件下代谢需求的协调。 (3)过渡因素：对环境胁迫的适应主要通过蛋白质的作用来实现，这些蛋白质又通过转录因子（TF）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，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中具有重要的代谢作用。这些都是生活在低代谢状态下的动物的关键需求，但迄今为止，这些TF尚未得到分析。 (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焦点，特别强调通过可逆的蛋白质磷酸化来控制糖酵解和其他细胞溶质酶。基于对两种线粒体酶的新研究，拟议的研究将重点转移到应激/MRD下的线粒体酶调节和可能是关键调节因子的潜在线粒体特异性修饰（例如戊二酰化）。总的来说，我们的提议将在我们对动物生化适应策略的了解方面取得新的进展。