METABOLIC ADAPTATIONS OF NEONATES TO EXTRAUTERINE LIFE

我们的长期目标是发展对 生理、细胞、生化和分子机制使 哺乳动物的新生儿在新陈代谢上变得独立。该项目 重点放在肝脏。肝细胞有一定程度的缺氧，相对 在子宫中静止。出生后，肝脏立即启动了一系列 新的代谢活动具有大量的能量需求，只有通过 完全胜任的有氧三磷酸腺苷合成的同步发展。 因此，肝脏线粒体功能的快速参与是一种 新生儿代谢适应的重要特征。以前的工作 证实了腺嘌呤核苷酸池大小的增加 线粒体通过从细胞质中的净摄取发生在 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通过以下方式实现的 线粒体ATP-mg/PI载体与PI的交换。由此产生的 基底腺嘌呤核苷酸浓度的增加被假设为 使ATP供应(通过激活ATP合成酶)与ATP需求匹配(通过 刺激中间代谢的反应，这些反应定位于 矩阵)。这种供需的协调调节保护了细胞 在出生时危险的低氧-正常氧转变过程中的ATP。 出生后基质腺嘌呤核苷酸含量的增加也是 被认为是线粒体生物发生的启动刺激 新生儿的肝脏。下一个项目期有四个目标：(1) 对ATP-mg/PI作用机制和调控的严格假设检验 载体；(2)测定生理信号和细胞内 ATP-mg/PI载体转运功能的调控机制 MT肝细胞；(3)检验基质腺嘌呤核苷酸假设 含量协调调节a)ATP合成酶活性和b) 通过对腺嘌呤核苷酸的作用实现糖异生和尿失禁 依赖于基质反应，这种调节保护细胞ATP 以及(4)研究细胞色素氧化酶基因如何 在线粒体生物发生的背景下，表达受到调控 新生大鼠肝脏。这些研究是与医疗管理有关的 因各种原因(如呼吸窘迫、产妇 糖尿病，呼吸酶。缺陷)面临着无法 按期发展肝脏的代谢和生物能量功能。

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.