Stable isotopic and metabolomic studies in a model of lactic acidosis tolerance

乳酸性酸中毒耐受模型中的稳定同位素和代谢组学研究

• 批准号: 8434667
• 负责人: DANIEL E WARREN
• 金额: $ 42.85万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434667
• 关键词: Acetyl Coenzyme A; Acidosis; Aerobic; Affect; Air; Animal Model; Animals; Anoxia; Biochemistry; Biological; Blood; Body Temperature; Breathing; Buffers; Carbon; Carbon Dioxide; Consumption; Data Analyses; Dependence; Depressed mood; Detection; Fatty Acids; Future; Genetic; Genome; Glucose; Glycogen; Glycolysis; Goals; Human; Hyperglycemia; Kinetics; Label; Lactic Acidosis; Lactic acid; Lead; Light; Liver; Mammals; Metabolic; Metabolic Diseases; Metabolic acidosis; Metabolic stress; Metabolism; Methodology; Modeling; Molecular Biology; Muscle; Oxygen; Oxygen Consumption; Paint; Plasma; Process; Recovery; Recycling; Relative (related person); Research; Resistance; Rest; Rodent; Temperature; Time; Tissues; Tracer; Turtles; Vertebrates; Work; deprivation; extracellular; human disease; in vivo; innovation; insight; killings; meetings; metabolic abnormality assessment; metabolic depression; metabolomics; novel; oxidation; oxygen transport; prevent; response; stable isotope; tool; warm temperature

DESCRIPTION (provided by applicant): The goal of the proposed research is to use the profoundly anoxia and acidosis-resistant painted turtle to better understand the basic processes underlying vertebrate anaerobic metabolism, which is closely associated with a large number of human metabolic diseases, particularly those involving impaired oxygen transport. Insights from conventional studies utilizing mammalian models of vertebrate anaerobic metabolism and subsequent aerobic recovery are limited by mammals' low tolerance to anoxia and lactic acidosis and the rapid metabolite turnover rates resulting from high metabolic rates, particularly in rodents. The painted turtle is the most anoxia-tolerant air-breathing vertebrate species known, has metabolic rates an order of magnitude lower than a similar sized mammal, and can accumulate lactic acid to concentrations 4-5x greater than the lethal limit for mammals. With the long-term goal of better understanding the mechanisms underlying anaerobic metabolism and metabolite fluxes during recovery, our aims are to: 1) Characterize the plasma and tissue metabolomic profiles during and following anoxia, 2) Investigate the metabolic fates of lactate within the metabolome during and after anoxia, and 3) Determine what substrates fuel normal and recovery metabolism. The interaction of temperature-induced changes in metabolic rate on all of these processes will also be investigated. This work represents an innovative approach to studies of anaerobic metabolism by combining, for the first time, an ideal model organism for studies of metabolic stress with stable isotopic and metabolomics approaches. We expect to gain a deeper understanding of the relationship between metabolic rate and lactate kinetics in vertebrates and to gain new and general insights into these clinically important metabolic processes. PUBLIC HEALTH RELEVANCE: This study will provide new insights into the mechanisms underlying anaerobic metabolism and lactic acid clearance in vertebrates. Ultimately, this will contribute to our broader understanding of the causes and consequences of many metabolic diseases in humans, particularly those involving metabolic acidosis and those related to limitations in oxygen transport.

描述（由申请人提供）：拟议研究的目标是使用深度缺氧和抗酸中毒的彩龟，以更好地了解脊椎动物无氧代谢的基本过程，这与大量人类代谢疾病密切相关，特别是那些涉及氧转运受损的疾病。利用脊椎动物无氧代谢和随后的有氧恢复的哺乳动物模型的常规研究的见解受到哺乳动物对缺氧和乳酸酸中毒的低耐受性以及由高代谢率引起的快速代谢物周转率的限制，特别是在啮齿动物中。 彩龟是已知的最耐缺氧的呼吸脊椎动物，其代谢率比类似大小的哺乳动物低一个数量级，并且可以积累乳酸，其浓度比哺乳动物的致死极限高4- 5倍。长期目标是更好地了解恢复过程中厌氧代谢和代谢物通量的机制，我们的目标是：1）表征缺氧期间和缺氧后的血浆和组织代谢组学特征，2）研究缺氧期间和缺氧后代谢组中乳酸的代谢命运，3）确定哪些底物促进正常和恢复代谢。还将研究温度引起的代谢率变化对所有这些过程的相互作用。 这项工作代表了一种创新的方法来研究厌氧代谢相结合，第一次，一个理想的模式生物与稳定同位素和代谢组学方法的代谢应激研究。我们期望获得更深入的了解代谢率和乳酸动力学之间的关系，在脊椎动物，并获得新的和一般的见解，这些临床上重要的代谢过程。 公共卫生关系：本研究将为脊椎动物无氧代谢和乳酸清除的机制提供新的见解。最终，这将有助于我们更广泛地了解人类许多代谢性疾病的原因和后果，特别是那些涉及代谢性酸中毒和与氧运输限制有关的疾病。