Molecular Basis of Preconditioning

预处理的分子基础

• 批准号: 6804329
• 负责人: D. K SRIVASTAVA
• 金额: $ 21.15万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804329
• 关键词: acetyl coA; acyl coA dehydrogenases; biological models; cardiovascular disorder prevention; cytoprotection; enzyme activity; enzyme substrate complex; free radical oxygen; heart disorder chemotherapy; ion channel blocker; ischemia; ischemic preconditioning; laboratory rat; membrane channels; mitochondria; molecular biology; oxidation; pharmacokinetics; potassium channel; thermodynamics

DESCRIPTION (provided by applicant): The long term goal of the proposed research is to deleneate the molecular basis of ischemic and pharmacological preconditioning. It has been repeatedly observed that short period of ischemia protects heart tissues from prolonged ischemic insult, and such an effect is mimicked by a variety of pharmacological agents. Although preconditioning and its blockage are believed to be mediated via openining and closing of the mitochondrial K(ATP) channels, respectively, overall mechanistic feature is not unequivocal. Our preliminary data suggest 5-hydroxydecanoyI-CoA (the CoA-derivative of the potential K(ATP) channel blocker 5-hydroxydecanoic acid) is metabilized via medium chain acyI-CoA dehydrogenase, as well as by the subsequent enzymes of the mitochondrial fatty acid oxidative pathway. The proposed research is based on our hypothesis that the origin of pharmacological preconditioning and its blockage lies in the modulation of enzyme activities of the mitochondrial pathways (viz., fatty acid oxidation and TCA cycle) and the electrontransfer system. The specific aims of the proposed research are: (1) To elucidate the detailed mechanism for the metabolism of 5-hydroxydecanoyI-CoA (5-HD-CoA) via the enzymes of the mitochondrial oxidative pathway, (2) To determine the effects of 5-HD-CoA and its metabolized products on selected mitochrondrial enzymes, and (3) To investigate the mechanism of production/suppression of reactive oxygen species (ROS) under the influence of selective preconditioning modulators. These specific aims will be accomplished by employing the techniques of enzyme kinetics, thermodynamics, model building studies involving isolated enzymes and intact mitochonrial preparations. The outcomes of the proposed studies will throw light on the molecular basis of preconditioning and may lead to the development of cardioprotective drugs.

描述（由申请人提供）：拟议研究的长期目标是深入研究缺血和药理预处理的分子基础。反复观察到，短时间缺血可保护心脏组织免受长时间缺血损伤，这种作用可被多种药物模拟。虽然预适应及其阻断被认为分别通过线粒体K（ATP）通道的打开和关闭介导，但总体机制特征尚不明确。我们的初步数据表明，5-羟基decanoyi - coa（潜在K（ATP）通道阻滞剂5-羟基decanoic酸的辅酶a衍生物）通过中链acyI-CoA脱氢酶以及线粒体脂肪酸氧化途径的后续酶代谢。提出的研究是基于我们的假设，即药物预处理及其阻断的起源在于线粒体途径（即脂肪酸氧化和TCA循环）和电子传递系统的酶活性的调节。本研究的具体目的是：(1)阐明5-羟基decanoyi - coa （5-HD-CoA）通过线粒体氧化途径的酶代谢的详细机制；(2)确定5-HD-CoA及其代谢产物对选定线粒体酶的影响；(3)研究选择性预处理调节剂影响下活性氧（ROS）产生/抑制的机制。这些具体目标将通过采用酶动力学、热力学、涉及分离酶和完整线粒体制备的模型构建研究的技术来实现。这些研究的结果将揭示预处理的分子基础，并可能导致心脏保护药物的开发。