MYOCARDIAL PROTECTION WITH A1 RECEPTOR OVEREXPRESSION

A1 受体过度表达的心肌保护

• 批准号: 6183840
• 负责人: Gaynell PAUL MATHERNE
• 金额: $ 27.41万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183840
• 关键词: adenosine; calcium flux; cellular pathology; echocardiography; genetically modified animals; glucose metabolism; heart function; heart metabolism; laboratory mouse; myocardial ischemia /hypoxia; purinergic receptor; receptor expression; reperfusion

DESCRIPTION (adapted from the applicant's abstract): Myocardial damage from ischemia with coronary vascular disease causes significant morbidity and mortality. The investigators have been studying the effects of endogenous protective mechanisms, such as adenosine, to provide tolerance to ischemia. The investigators note that acting at A1 receptors, adenosine reduces ischemia-reperfusion injury and mediates ischemic preconditioning. In addition they state that the heart must also adapt to changing metabolic needs to avoid injury from imbalances in myocardial oxygen supply and demand. When the metabolic demands of the heart are greater than the oxygen supply (demand ischemia), the investigators indicate that adenosine acts via the A1 adenosine receptor to directly protect the myocardium. Thus, the investigators conclude that activation of A1 receptors can provide protection to the heart during bot ischemia and "demand ischemia". This proposal adopts the approach of overexpressing myocardial A1 adenosine receptors with transgenic techniques to enhance the intrinsic tolerance of the myocardium to ischemia reperfusion, and demand ischemia. The central hypothesis of this proposal is that a transgenic model of increased cardiac A1 receptors will have increased protection from ischemia- reperfusion and from decreases in the oxygen supply to demand ratio ("demand ischemia"). The long range goal is an integrated analysis of the role of A1 receptors in cardioprotection in order to identify the mechanism of this protection. The investigators will evaluate the functional, bioenergetic, biochemical, and ultrastructural response to ischemia in transgenic mice and will assess the mechanism(s) of A1 adenosine receptor-mediated myocardial protection by identifying the signaling pathways involved and evaluating the cellular mechanisms by assessing calcium transport and glucose metabolism.

描述（改编自申请人摘要）：心肌损伤 冠状动脉疾病引起的缺血 发病率和死亡率。 调查人员一直在研究 内源性保护机制，如腺苷， 提供对局部缺血的耐受性。调查人员指出，在A1 受体，腺苷减少缺血再灌注损伤，并介导 缺血预适应 此外，他们指出，心脏必须 也适应不断变化的代谢需求，以避免因失衡而受伤 在心肌氧供应和需求方面。 当新陈代谢的需求 心脏大于氧气供应（需求缺血）， 研究者指出腺苷通过A1腺苷受体起作用 直接保护心肌。 因此，调查人员得出结论， 激活A1受体可以保护心脏 在BOT缺血和“需求缺血”期间。 本提案通过了 心肌腺苷A1受体过表达的方法 转基因技术，以提高内在的耐受性， 心肌缺血再灌注，并要求缺血。 中央 这一建议的假设是，增加的转基因模型 心脏A1受体会增加对缺血的保护， 再灌注和氧供需比下降 （“需求缺血”）。长期目标是综合分析 A1受体在心脏保护中的作用，以确定 这种保护机制。 研究人员将评估 功能，生物能量，生物化学和超微结构反应， 转基因小鼠的缺血，并将评估A1的机制 腺苷受体介导的心肌保护作用 参与的信号通路和评估细胞机制， 评估钙转运和葡萄糖代谢。