METABOLIC ADAPTATIONS OF NEONATES TO EXTRAUTERINE LIFE

新生儿对宫外生活的代谢适应

• 批准号: 3314062
• 负责人: JUNE R APRILLE
• 金额: $ 12.1万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3314062
• 关键词: adenine nucleotides; adenosine triphosphate; age difference; bioenergetics; biological signal transduction; cytochrome oxidase; embryo /fetus cell /tissue; gene expression; gluconeogenesis; hydrogen transporting ATP synthase; hypoxia neonatorum; intracellular transport; laboratory rat; liver cells; liver metabolism; magnesium; mathematical model; mitochondria; newborn animals; nucleic acid biosynthesis; oxidative phosphorylation; oxygen tension; postpartum; tissue /cell culture

The long-term goal is to develop an integrated understanding of the physiological, cellular, biochemical, and molecular mechanisms that enable the mammalian neonate to become metabolically independent. The project focuses on liver. Hepatocytes are somewhat hypoxic and relatively quiescent in utero. Immediately after birth the liver initiates a host of new metabolic activities with large energy demands that can be met only by the coincident development of fully competent aerobic ATP synthesis. Therefore, the rapid engagement of mitochondrial function in liver is an important feature of metabolic adaptation in the newborn. Previous work established that an increase in the adenine nucleotide pool size in the mitochondrial compartment occurs by net uptake from the cytoplasm within a few hours after birth in response to postnatal tissue oxygenation and hormonal signals. The uptake of adenine nucleotides is brought about by exchange with Pi on the mitochondrial ATP-Mg/Pi carrier. The resulting increase in matrix adenine nucleotide concentration is hypothesized to match ATP supply (by activating ATP synthetase) with ATP demand (by stimulating reactions of intermediary metabolism that are localized in the matrix). This coordinate regulation of supply and demand protects cellular ATP during the precarious hypoxic-normoxic transition that occurs at birth. The postnatal increase in matrix adenine nucleotide content is also hypothesized to be an initiating stimulus for mitochondrial biogenesis in the newborn liver. For the next project period there are four aims: (1) To test rigorous hypotheses for the mechanism and regulation of the ATP-Mg/Pi carrier; (2) To determine the physiological signals and intracellular mechanisms that regulate the transport function of the ATP-Mg/Pi carrier in mt hepatocytes; (3) To test the hypothesis that matrix adenine nucleotide content coordinately regulates a) the activity of ATP synthetase and b) gluconeogenesis and ureagenesis through effects on adenine nucleotide dependent matrix reactions, and that this regulation protects cellular ATP during hypoxic episodes; and (4) To investigate how cytochrome oxidase gene expression is regulated in the context of mitochondrial biogenesis in newborn rat liver. These studies are relevant to the medical management of neonates who for various reasons (e.g. respiratory distress, maternal diabetes, respiratory enzyme. deficiencies) are at-risk for failure to develop metabolic and bioenergetic functions of the liver on schedule.

长期目标是全面了解 生理、细胞、生化和分子机制， 哺乳动物新生儿变得代谢独立。 项目 专注于肝脏。 肝细胞有些缺氧， 在子宫内静止出生后，肝脏立即启动一系列的 新的代谢活动需要大量的能量，只能通过以下方式来满足 完全有能力的有氧ATP合成的同步发展。 因此，肝脏中线粒体功能的快速参与是一个重要因素。 新生儿代谢适应的重要特征。 以前的工作 确定了腺嘌呤核苷酸池大小的增加， 线粒体隔室通过从细胞质中的净摄取而发生， 出生后几小时对出生后组织氧合的反应， 荷尔蒙信号 腺嘌呤核苷酸的摄取是由 与Pi在线粒体ATP-Mg/Pi载体上交换。 所得 假设基质腺嘌呤核苷酸浓度增加 使ATP供给（通过激活ATP合成酶）与ATP需求（通过 刺激中间代谢的反应，这些反应定位在 矩阵）。 这种供应和需求的协调调节保护了蜂窝 ATP在出生时发生的不稳定的缺氧-常氧过渡期间。 出生后基质腺嘌呤核苷酸含量的增加也是 假设是一个启动刺激线粒体生物合成， 新生的肝脏 在下一个项目期间，有四个目标：（1） 验证ATP-Mg/Pi机制和调节的严格假设 （2）确定生理信号和细胞内 调节ATP-Mg/Pi载体转运功能的机制 （3）为了验证基质腺嘌呤核苷酸 含量协调调节a）ATP合成酶的活性和B） 通过影响腺嘌呤核苷酸的代谢和尿素生成 依赖的基质反应，这种调节保护细胞ATP 探讨细胞色素氧化酶基因在缺氧过程中的作用。 在线粒体生物发生的背景下， 新生大鼠肝脏。这些研究与以下疾病的医疗管理有关： 新生儿由于各种原因（如呼吸窘迫，产妇 糖尿病呼吸酶缺陷）的风险， 按计划发展肝脏的代谢和生物能量功能。