The Role of phosphoenolpyruvate carboxykinase and reactive oxygen species in the

磷酸烯醇丙酮酸羧激酶和活性氧在

• 批准号: 8018129
• 负责人: Jason Earl Podrabsky
• 金额: $ 36.5万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018129
• 关键词: Acids; Address; Aerobic; Affect; Alanine; Amaze; Animals; Anoxia; Biochemical; Biochemical Pathway; Biology; Brain; Carbon; Cell Death; Cell physiology; Cells; Cessation of life; Characteristics; Citric Acid Cycle; Coupled; Cyprinodontidae; Cytoplasm; Data; Detection; Development; Diapause; Embryo; Embryonic Development; Engineering; Enzymes; Event; Exhibits; Exposure to; Fishes; Fluorescent Probes; Fundulus heteroclitus; Generations; Genetic; Genomics; Glycolysis; Guanosine Triphosphate; Heart; Heart Diseases; High Pressure Liquid Chromatography; Hour; Human; Human Development; Immunohistochemistry; Kinetics; Knowledge; Light; Mediating; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolism; Methodology; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; Natural Selections; Nature; Organism; Oxygen; Pattern; Phosphocreatine; Phosphoenolpyruvate Carboxylase; Physiological; Physiological Adaptation; Physiology; Process; Production; Protein Biosynthesis; Reactive Oxygen Species; Recovery; Reporting; Role; Sampling; Source; Stroke; Succinates; System; Testing; Time; Tissues; Vertebrates; Writing; Yolk Cell; base; brain cell; brain tissue; deprivation; embryo cell; enzyme activity; gamma-Aminobutyric Acid; heart cell; inhibitor/antagonist; inorganic phosphate; metabolomics; methylxanthine; mitochondrial membrane; novel; oxidation; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): Almost all organisms on Earth share the basic metabolic pathways that support anaerobic metabolism, and yet many organisms, including most vertebrates, cannot survive for long without molecular oxygen. Embryos of the annual killifish Austrofundulus limnaeus are an excellent model for investigating the mechanistic basis of anoxia-tolerance and anoxia-sensitivity in vertebrates. Embryos of A. limnaeus undergo a unique period of developmental dormancy called diapause. Recent evidence suggests that embryos of A. limnaeus have some very unique physiological adaptations that are associated with tolerance of long-term anoxia. Both dormant and actively developing embryos of A. limnaeus can survive for months without oxygen at 250C. Embryos of A. limnaeus display a massive depletion of ATP during the initial hours of anoxic exposure and lose their mitochondrial membrane potential during this same time frame. These two events are typically associated with cell death in other vertebrate cells, but embryos of A. limnaeus quickly recover from these drastic changes in mitochondrial physiology and energetics. These observations imply that cells of A. limnaeus embryos have some extraordinary characteristics compared to other vertebrates, and even to other vertebrates that exhibit substantial tolerance of anoxia. I will identify the metabolic pathways that support anoxia tolerance in isolated cells of A. limnaeus, assess mitochondrial function and energetics during anoxia and recovery from anoxia, and test the hypothesis that an alternate metabolic pathways supported by the enzyme phosphoenolpyruvate carboxykinase is critical for the survival of anoxia. By using the integrative approaches outlined in the proposal we can hopefully create a more complete picture of the cellular physiology of anoxia-tolerance in the cells if this exceptional vertebrate extremophile. PUBLIC HEALTH RELEVANCE: Heart disease and stroke are responsible for the vast majority of deaths in the developed world. The extreme sensitivity of human heart and brain tissue to lack of oxygen is poorly understood at the cellular level. By understanding the cellular mechanisms that support extreme anoxia tolerance in embryos of the annual killifish, Austrofundulus limnaeus, we may be able to develop treatments to mediate or prevent the damaging effects of heart attacks and strokes to humans.

描述（由申请人提供）：地球上几乎所有生物都有支持厌氧代谢的基本代谢途径，然而，如果没有分子氧，包括大多数脊椎动物在内的许多生物（包括大多数脊椎动物）无法生存。每年的杀伤力元素limnaeus的胚胎是研究脊椎动物中缺氧和缺氧 - 敏感性的机理基础的绝佳模型。 limnaeus的胚胎经历了一个独特的发育休眠时期，称为尿布劳。最近的证据表明，Limnaeus的胚胎具有一些非常独特的生理适应性，这些适应与长期缺氧的耐受性有关。休眠和积极发育的limnaeus胚胎都可以在250°C时生存几个月。 limnaeus的胚胎显示出在缺氧的最初小时内显示ATP的大量耗竭，并在同一时间范围内失去了线粒体膜电位。这两个事件通常与其他脊椎动物细胞中的细胞死亡有关，但是limnaeus的胚胎迅速从线粒体生理和能量学的这些急剧变化中恢复过来。这些观察结果表明，与其他脊椎动物相比，与其他脊椎动物相比，Limnaeus胚胎的细胞具有一定的特征，甚至具有表现出很大的缺氧耐受性的其他脊椎动物。我将确定支持在Limnaeus的孤立细胞中支持缺氧耐受性的代谢途径，评估缺氧期间的线粒体功能和能量学并从缺氧中恢复，并测试假设，即由磷酸烯醇酮酮酶羧基酶基因酶羧基酶酶酶酶的酶含量至关重要。通过使用该提案中概述的综合方法，如果这种特殊的脊椎动物极端粒子，我们可以对细胞中缺氧的细胞生理学的细胞生理图更完整。 公共卫生相关性：心脏病和中风负责发达国家的绝大多数死亡。在细胞水平上，人心脏和脑组织对缺氧的极端敏感性很少。通过了解支持年度Killifish，Austrofundulus limnaeus的胚胎中极端缺氧耐受性的细胞机制，我们可能能够开发治疗方法以介导或防止对人类的心脏病发作和中风的损害影响。