METABOLIC ADAPTATIONS OF NEONATES TO EXTRAUTERINE LIFE

新生儿对宫外生活的代谢适应

• 批准号: 3314066
• 负责人: JUNE R APRILLE
• 金额: $ 15.75万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3314066
• 关键词: adenine nucleotides; adenosine triphosphate; animal birth weight; biological signal transduction; biological transport; birth; brain metabolism; cell differentiation; gestational diabetes mellitus; glucagon; gluconeogenesis; heart metabolism; human tissue; insulin; kidney metabolism; laboratory rabbit; laboratory rat; liver metabolism; metabolism; mitochondria; mitochondrial membrane; newborn animals; nucleic acid biosynthesis; oxidative phosphorylation; phosphoenolpyruvate carboxylase; postpartum; protein biosynthesis; respiratory distress syndrome of newborn; urea cycle

The objective is to understand the cellular and biochemical events that lead to successful metabolic adaptation in early postnatal life. We have shown that perinatal changes in insulin/glucagon andd tissue pO2 regulate the sudden net uptake of adenine nucleotides (ADN) from the liver cytosol into the mitochondria, resulting in a large increase in the matrix ATP+ADP+AMP pool size within a few hours after birth. Mitochondrial ADN uptake occurs via a novel transport mechanism that we propose to characterize in detail. In addition we will investigate the hypothesis that the increased matrix ADN concentration is the initiating signal for an extended program of metabolic development that unfolds subsequently. One immediate effect would be the stimulation (probably by mass action) of key ADN-dependent reactions that are localized in the matrix, e.g.: oxidative phosphorylation, pyruvate carboxylation, short chain fatty acid activation, and citrulline synthesis, that promotes the restoration of energy homeostasis during the critical period of metabolic adjustment immediately after birth. Most interesting is the prospect that early postnatal proliferation of mitochondria is regulated by this mechanism via stimulation of the ADN-dependent matrix reactions required for mitochondrial biogenesis, e.g.: mitochondrial synthesis of cardiolipin, nucleic acids, and protein, and translocation of nuclear-encoded precursor proteins into the mitochondria. Mitochondrial proliferation may in turn be a prerequisite for the optimum development of specialized pathways such as gluconeogenesis, urea synthesis, and fatty acid oxidation, all of which have nuclear-encoded enzymes assigned to the mitrochondria compartment. Mitochondrial proliferation may also be permissive for the onset of postnatal cell division. The temporal sequence of these events, their mechanistic details, and regulatory interrelationships will be studied in newborn rats and rabbits, in vivo and in hepatocytes and isolated mitochondria prepared at various stages of postnatal development. Given that the important physiological signals at parturition are increased pO2 and decreased insulin/glucagon, the effect of respiratory distress and maternal diabetes on normal development will receive special attention.

目的是了解细胞和生化事件 导致出生后早期成功的代谢适应。 我们有 研究表明，围产期胰岛素/胰高血糖素和组织 pO2 的变化可调节 从肝细胞质中突然净摄取腺嘌呤核苷酸 (ADN) 进入线粒体，导致基质大量增加 出生后几个小时内 ATP+ADP+AMP 池大小。 线粒体ADN 我们建议通过一种新颖的运输机制进行吸收 详细表征。 此外，我们将研究假设 基质 ADN 浓度的增加是 随后展开的代谢发育的扩展程序。 一 直接效果将是关键的刺激（可能是通过集体行动） 位于基质中的 ADN 依赖性反应，例如：氧化 磷酸化、丙酮酸羧化、短链脂肪酸活化、 和瓜氨酸合成，促进能量恢复 代谢关键期立即调整体内平衡 出生后。 最有趣的是产后早期的前景 线粒体的增殖受此机制的调节 刺激 ADN 依赖性基质反应所需 线粒体生物发生，例如：心磷脂的线粒体合成， 核酸、蛋白质以及核编码前体的易位 蛋白质进入线粒体。 线粒体增殖可能反过来 专业途径最佳发展的先决条件，例如 糖异生、尿素合成和脂肪酸氧化，所有这些 具有分配给线粒体室的核编码酶。 线粒体增殖也可能允许发生 出生后细胞分裂。 这些事件的时间顺序、它们的 机制细节和监管相互关系将在 新生大鼠和兔的体内和肝细胞以及分离的 线粒体在出生后发育的各个阶段制备。 给定 分娩时重要的生理信号是氧分压增加 和胰岛素/胰高血糖素减少、呼吸窘迫的影响和 孕产妇糖尿病对正常发育的影响将受到特别关注。