METABOLIC ADAPTATIONS OF NEONATES TO EXTRAUTERINE LIFE

新生儿对宫外生活的代谢适应

• 批准号: 3314065
• 负责人: JUNE R APRILLE
• 金额: $ 15.18万
• 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/3314065
• 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; 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.

其目的是了解细胞和生化事件 导致在出生后早期成功的新陈代谢适应。我们有 显示围产期胰岛素/胰高血糖素的变化和组织中PO2的调节 肝细胞质腺嘌呤核苷酸(ADN)的突然净摄取 进入线粒体，导致基质大量增加 ATP+ADP+AMP池大小在出生后几小时内。线粒体ADN 摄取通过一种新的运输机制发生，我们建议 详细描述。此外，我们还将研究这一假设 增加的基质ADN浓度是一种 随后展开的新陈代谢发展的扩展计划。一 立竿见影的效果将是Key的刺激(可能是通过集体行动) 定位于基质中的ADN依赖的反应，例如：氧化 磷酸化，丙酮酸羧化，短链脂肪酸活化， 和瓜氨酸的合成，促进能量的恢复 即刻代谢调整关键期的动态平衡 出生后。最有趣的是早产儿的前景 线粒体的增殖是通过这种机制来调节的 刺激依赖ADN的基质反应所需的 线粒体生物发生，例如：线粒体合成心磷脂， 核酸、蛋白质和核编码前体的易位 蛋白质进入线粒体。线粒体的增殖可能反过来又是 优化发展专门路径的先决条件，例如 糖异生、尿素合成和脂肪酸氧化，所有这些 有核编码的酶被分配到线粒体内。 线粒体的增殖也可能是发病的原因。 出生后细胞分裂。这些事件的时间顺序、它们的 机械性细节和监管相互关系将在 新生大鼠和兔，体内和肝细胞内，以及分离的 线粒体是在出生后发育的不同阶段准备的。vt.给出 分娩时重要的生理信号是氧分压升高 降低胰岛素/胰高血糖素，呼吸窘迫和 产妇糖尿病对正常发育的影响将受到特别关注。