ADENINE NUCLEOTIDE METABOLISM IN RENAL ISCHEMIA

肾缺血中的腺嘌呤核苷酸代谢

基本信息

批准号：
3245887
负责人：
NORMAN J SIEGEL
金额：
$ 28.51万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-07-01 至 1995-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3245887
关键词：
adenine nucleotides adenosinetriphosphatase brush border membrane calcium flux cell biology cytoskeleton gap junctions laboratory rat membrane proteins nuclear magnetic resonance spectroscopy nucleotide metabolism oxygen consumption renal failure renal ischemia /hypoxia sodium potassium exchanging ATPase stress proteins

项目摘要

The goal of this research proposal is to advance our understanding of the cellular and metabolic alterations which are responsible for the initiation and recovery from acute renal failure and to obtain new insight which will be applicable in the clinical setting. This proposal is designed to provide new information concerning the effects of alterations in adenine nucleotides metabolism in renal tubular cells. We propose: a) to determine the hierarchy of cellular dysfunction in response to adenine nucleotide depletion and b) to define the role of de novo purine synthesis in the post-ischemic recovery of renal ATP. To evaluate these questions, we will employ an integrated approach in which investigations will be carried out in animal preparations in vivo as well as suspensions of tubular segments in vitro. In vivo stuies will evauate renal function and utilize 31P NMR spectroscopy to determine the pattern of alterations in renal ATP during and after an insult. In vitro studies will evaluate cellular and molecular components of the epithelial cell injury. The cellular aspect will define changes in intracellular calcium, phospholipid profile, and morphological changes. The metabolic components will evaluate adenine nucleotides and breakdown products, and oxygen consumption in tubular suspensions under basal, stimulated, and inhibited conditions. The molecular aspects of these studies will focus on the role of cytoskeletal elements, brush-border proteins, tight-junction protein, Na/K-ATPase, and stress proteins in the restoration of cell integrity. In this manner, we propose to determine the cellular, metabolic, and molecular basis of the morphological and physiologic alterations which occur during altered adenine nucleotide metabolism.

本研究计划的目标是增进我们对细胞和代谢的改变是造成急性肾功能衰竭的起始和恢复以及获得新的洞察力将适用于临床环境。这个提议旨在提供有关影响的新信息肾小管细胞腺嘌呤核苷酸代谢的改变。我们建议：a) 确定细胞功能障碍的等级对腺嘌呤核苷酸消耗的反应和 b) 定义的作用肾 ATP 缺血后恢复中的从头嘌呤合成。到评估这些问题，我们将采用综合方法将在动物体内进行研究以及体外管状节段的悬浮液。体内研究将评估肾功能并利用 31P NMR 光谱来确定损伤期间和之后肾脏 ATP 的变化模式。在体外研究将评估细胞和分子成分上皮细胞损伤。细胞方面将定义变化细胞内钙、磷脂谱和形态变化。代谢成分将评估腺嘌呤核苷酸和分解产品，以及基础管状悬浮液中的耗氧量，刺激条件和抑制条件。这些的分子方面研究将集中于细胞骨架元素、刷状缘的作用蛋白质、紧密连接蛋白、Na/K-ATP酶和应激蛋白恢复细胞完整性。通过这种方式，我们建议确定细胞、代谢和分子基础改变过程中发生的形态和生理变化腺嘌呤核苷酸代谢。