MYOCARDIAL PROTECTION WITH A1 RECEPTOR OVEREXPRESSION

描述(改编自申请人的摘要)：心肌损伤 由缺血合并冠状动脉血管疾病引起的显著 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，对 提供对缺血的耐受。调查人员注意到，在A1处采取行动 受体，腺苷减轻缺血再灌注损伤并介导 缺血预适应。此外，他们还说心脏必须 还能适应不断变化的新陈代谢需求，以避免不平衡造成的伤害 在心肌氧供应和需求方面。当人体的新陈代谢需求 心脏大于供氧(需氧量缺血)， 研究人员指出，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 A1受体的激活可以为心脏提供保护 在BOT缺血和“需求缺血”期间。这项建议采用了 心肌A1腺苷受体过表达的研究进展 提高植物内在耐受性的转基因技术 心肌要缺血再灌流，需要缺血。中环 这一建议的假设是，转基因模型增加了 心脏A1受体将增强对缺血的保护- 再灌流和氧供需比下降 (“需求缺血”)。长期目标是对 A1受体在心脏保护中的作用 这种保护的机制。调查人员将评估 功能性、生物能量学、生化和超微结构反应 转基因小鼠脑缺血，并将探讨A1的作用机制(S) 腺苷受体介导的心肌保护作用 参与的信号通路和评估的细胞机制 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.