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RENAL AMMONIAGENESIS: 15NH3 STUDIES WITH GC-MS

肾氨生成：使用 GC-MS 进行 15NH3 研究

基本信息

批准号：
3233010
负责人：
ITZHAK NISSIM
金额：
$ 16.41万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-12-01 至 1991-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3233010
关键词：
acid base balance acidity /alkalinity acidosis alkalosis alpha ketoglutarate aminoacid metabolism ammonia citrate synthase gluconeogenesis glucose glutamate ammonia ligase glutamate dehydrogenase glutamates homeostasis kidney metabolism laboratory rat mass spectrometry radiotracer

项目摘要

This proposal entails a comprehensive examination of the mechanism(s) controlling renal amino acid metabolism, ammoniagenesis and gluconeogenesis in various acid base states. The work will address five primary themes: (1) the metabolic signals initiating augmented ammoniagenesis in acidosis; (2) the rate limiting metabolic pathway(s) for ammonia production; (3) the role of effectors and/or inhibitors of ammoniagenesis on the underlying biochemistry; (4) the putative relationship between renal ammonia and glucose formation; (5) the biochemical adaptation occurring both during the induction of and recovery from acidosis and alkalosis. The core hypothesis of the work is that diminished flux through the citrate synthetase pathway is an initial step in a coordinated sequence of events leading to an increased rate of ammoniagenesis in acidosis. A corollary hypothesis is that the diminution of the alpha-ketoglutarate pool secondary to reduced flux through citrate synthetase is accompanied by enhanced flux through glutamate dehydrogenase toward oxidative deamination of glutamate with the release of NH3. We also will explore the possibility that the augmentation of ammoniagenesis and gluconeogenesis in acidosis are (or are not) inter-dependent phenomenon subject to common metabolic signals and controls, with the increase of glucose production providing an outlet for glutamate carbon. The significance of diminished flux through the glutamine synthetase reaction in abetting HN3 production will be studied as well. These topics will examined by incubating isolated rat renal tubules with 15N and/or 13C labelled precursors in the presence and absence of metabolic modulators and/or inhibitors. Subsequent determination of important precursor-product relationships and flux rates will be made using gas chromatography-mass spectrometry and/or nuclear magnetic resonance spectroscopy. The data so obtained will be of scientific import by deepening our understanding of renal ammoniagenesis in response to perturbations of hydrogen ion homeostasis. The project will evaluate such adaptations in terms of the stage of acidosis or alkalosis, i.e., during the induction of or recovery from either state.

这一建议要求全面审查控制肾氨基酸代谢的机制，在各种酸碱状态下的氨生成和氨异生作用。这项工作将涉及五个主要主题：（1）代谢在酸中毒中启动增强的氨生成的信号;（2）用于氨产生的限速代谢途径;（3）产氨作用的效应物和/或抑制物对基础生物化学;（4）之间的假定关系肾氨和葡萄糖的形成;（5）生化在诱导和恢复期间发生的适应因为酸中毒和酸中毒这项工作的核心假设是通过柠檬酸合成酶途径的流量减少是协调的一系列事件中的初始步骤，酸中毒时产氨率增加。一个推论假设α-酮戊二酸池的减少其次是通过柠檬酸合成酶的流量减少，伴随着通过谷氨酸脱氢酶的通量增加朝向谷氨酸的氧化脱氨作用， NH3 我们还将探讨这种可能性，酸中毒中的产氨作用和产氨异生作用是（或不是）受共同代谢信号影响的相互依赖现象与对照组相比，葡萄糖产量的增加提供了谷氨酸碳出口。通量减少的意义通过谷氨酰胺合成酶反应，生产也将进行研究。这些主题将通过孵育离体大鼠肾小管与15 N和/或13 C标记的前体，以及不存在代谢调节剂和/或抑制剂。后续重要子产品的确定关系和流量率将使用气体色谱-质谱和/或核磁共振共振光谱学这样获得的数据将是科学的，通过加深对肾氨生成的认识，对氢离子稳态扰动的反应。的该项目将评估这种适应的阶段，酸中毒或酸中毒，即，在诱导或恢复期间任何一个州。