METABOLIC ADAPTATIONS OF NEONATE TO EXTRAUTERINE LIFE

新生儿对宫外生活的代谢适应

• 批准号: 3314063
• 负责人: JUNE R APRILLE
• 金额: $ 13.44万
• 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 1986-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3314063
• 关键词: adenine nucleotides; adenosine triphosphate; animal birth weight; biological transport; birth; gluconeogenesis; liver metabolism; metabolism; mitochondria; mitochondrial membrane; newborn animals; oxidative phosphorylation; phosphoenolpyruvate carboxylase; postpartum; respiratory distress syndrome of newborn

Within minutes or hours of parturition, the maturation of pathways for oxidative phosphorylation, and the onset of significant rates of gluconeogenesis, are important metabolic adjustments required for an adequate neonatal defense against hypoglycemia. Preliminary studies have shown that, in rat and rabbit liver, right after birth, there is a sudden influx of adenine nucleotides from the cytosol into the mitochondria. This is correlated with the development of maximum rates of coupled respiration, and also with the activation of pyruvate carboxylase, the rate-limiting enzyme for gluconeogenesis at birth. These findings suggest a unifying hypothesis to explain how gluconeogenesis, and an adequate rate of ATP synthesis to support it, develop simultaneously within 1-2 hours without new enzyme synthesis: It is proposed that a stimulus associated with parturition triggers the influx of adenine nucleotides into the matrix compartment via a novel transport mechanism that regulates unidirectional movement of ATP and ADP across the inner mitochondrial membrane. As a result, the matrix adenine nucleotide pool size is rapidly increased in magnitude. Any enzymes localized in the matrix, which are also adenine nucleotide-dependent, may thus become suddenly active. Affected reactions include at least those of oxidative phosphorylation (ADP-dependent) and pyruvate carboxylase (ATP-dependent) and this may account for a 3-4 fold increase in gluconeogenesis. Experiments are proposed to test this hypothesis further and to understand the mechanistic details at the cellular-biochemical level. Specific areas to be investigated include: identification of the initiating physiological signals at birth, characterization of the novel ATP, ADP transport mechanism in he mitochondria; the basis for sensitivity of specific matrix reactions to alterations in the ATP+ADP pool size; and the relationship of over-all gluconeogenic rates in isolated hepatocytes to changes in the matrix adenine nucleotide pool size. There are reasons to suspect that neonatal hypoglycemia associated with maternal diabetes, respiratory distress, or prematurity may be caused by a delay in the postnatal influx of adenines into the matrix (which in turn would delay the acture postnatal activation of gluconeogenesis according to the hypothesis proposed;) this idea also will be investigated in animal models as part of this proposal.

在分娩后的几分钟或几小时内， 氧化磷酸化，和发病率显着的 代谢调节是一种重要的代谢调节， 新生儿对低血糖的充分防御。 初步研究已经 结果表明，在大鼠和兔子的肝脏中，刚出生后， 腺嘌呤核苷酸从胞质液流入线粒体。 这 与耦合呼吸最大速率的发展相关， 丙酮酸羧化酶的激活， 在出生的时候就有了这种酶。 这些发现表明， 一个解释植物共生的假说，以及一个足够的ATP速率 合成，以支持它，同时发展在1-2小时内， 新酶的合成：有人提出，刺激与 分娩触发腺嘌呤核苷酸流入基质 通过一种新的运输机制，调节单向 ATP和ADP穿过线粒体内膜的运动。 作为 结果，基质腺嘌呤核苷酸池的大小在 大小 任何位于基质中的酶，也就是腺嘌呤 依赖于核苷酸的，因此可能突然变得活跃。 受影响的反应 包括氧化磷酸化（ADP依赖性）， 丙酮酸羧化酶（ATP依赖性），这可能占3-4倍 增加再生能力。 提出实验来验证这一点 进一步的假设，并了解机械的细节， 细胞生化水平。 需要调查的具体领域包括： 识别出生时的起始生理信号， 对肝细胞ATP、ADP转运新机制的研究 线粒体;特异性基质反应敏感性的基础 ATP+ADP池大小的改变;以及总体 分离肝细胞对基质变化的致瘤率 腺嘌呤核苷酸池大小。 有理由怀疑新生儿 与母体糖尿病、呼吸窘迫或 早产可能是由于出生后腺嘌呤流入延迟引起的 进入基质（这反过来会延迟出生后激活的实际时间 根据所提出的假设;）这个想法也 将在动物模型中进行研究，作为本提案的一部分。