MYOCARDIAL PROTECTION WITH A1 RECEPTOR OVEREXPRESSION

描述（改编自申请人的摘要）：心肌损伤 冠状血管疾病引起的缺血会导致严重的 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）的作用 提供对缺血的耐受性。调查人员指出，在 A1 行动 受体、腺苷可减轻缺血再灌注损伤并介导 缺血预处理。 此外，他们还指出，心脏必须 还适应不断变化的代谢需求，以避免因不平衡而受伤 心肌氧的供应和需求。 当代谢需求 心脏的供氧量大于供氧量（需求缺血）， 研究人员表明腺苷通过 A1 腺苷受体发挥作用 直接保护心肌。 因此，调查人员得出结论 A1 受体的激活可以为心脏提供保护 在机器人缺血和“需求缺血”期间。 本提案采用 过表达心肌A1腺苷受体的方法 转基因技术增强内在耐受性 心肌要缺血再灌注，又需求缺血。 中央 该提案的假设是增加的转基因模型 心脏 A1 受体将增强对缺血的保护 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。 调查人员将评估 功能、生物能量、生化和超微结构反应 转基因小鼠缺血并评估 A1 的机制 通过识别腺苷受体介导的心肌保护 涉及的信号通路并通过以下方式评估细胞机制 评估钙转运和葡萄糖代谢。

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.