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; 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）：拟议的研究的目的是使用深刻的缺氧和抗酸中毒的涂有油漆的乌龟来更好地了解脊椎动物厌氧代谢的基本过程，该过程与大量的人类代谢性疾病密切相关，尤其是涉及氧气运输受损的人。传统研究的见解，利用脊椎动物厌氧代谢的哺乳动物模型和随后的有氧恢复受到哺乳动物对缺氧和乳酸酸中毒的低耐受性的限制，以及由于啮齿动物的高代谢率而引起的快速代谢率。 涂有油漆的乌龟是已知的最耐用空气呼吸脊椎动物，其代谢率比相似大小的哺乳动物低的数量级，并且可以将乳酸累积到浓度4-5x的浓度大于哺乳动物的致命极限。 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.还将研究温度诱导的所有这些过程中代谢率变化的相互作用。 这项工作代表了一种创新的方法，用于研究厌氧代谢的研究，首次通过稳定的同位素和代谢组学方法结合了一种理想的模型生物体来研究代谢应激的研究。我们希望对脊椎动物中的代谢率和乳酸动力学之间的关系有更深入的了解，并对这些临床上重要的代谢过程获得新的和一般的见解。 公共卫生相关性：这项研究将为脊椎动物中厌氧代谢和乳酸清除率提供的机制提供新的见解。最终，这将有助于我们对许多代谢性疾病的原因和后果的更广泛理解，尤其是涉及代谢性酸中毒的人以及与氧气转运的限制有关的疾病。