Ischemia-Reperfusion in A2A and A2B Knockout Hearts

A2A 和 A2B 敲除心脏的缺血再灌注

• 批准号: 7094071
• 负责人: R RAY MORRISON
• 金额: $ 12.47万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094071
• 关键词: biological signal transduction; gene targeting; genetically modified animals; heart function; laboratory mouse; myocardial ischemia /hypoxia; potassium channel; purinergic receptor; receptor expression; reperfusion

DESCRIPTION (provided by applicant): The primary objective of this proposal is the development of the principal investigator into an independent clinician scientist in the field of cardiovascular disease. The applicant is a pediatric critical care physician who actively participates in basic science research albeit with limited time away from clinical duties (35%). If funded, this award will allow 75% time for research training and pursuit of specific scientific aims. Under the sponsorship of a well-recognized adenosine pharmacologist, the proposal includes a curriculum of graduate level courses, regularly scheduled scientific seminars, attendance at national meetings, training in scientific techniques, and further involvement in the mentoring of graduate students. Within the fully supportive setting of a university-based school of medicine, a multidisciplinary advisory committee of established scientists and clinician scientists will guide the career development of the principal investigator. The proposed research will examine the relative roles of adenosine A2A and A2B receptors in myocardial tolerance to ischemia-reperfusion. Adenosine is a "retaliatory metabolite" released during imbalances of metabolic supply and demand that exerts cardioprotective responses through activation of at least four different receptor subtypes. Clarifying the contribution(s) of each adenosine receptor subtype in response to ischemia-reperfusion remains an essential step in developing potential pharmacologic therapies for the clinical management of heart disease. While A2A receptors are primarily responsible for regulation of coronary flow, their contribution to protection from ischemia-reperfusion is just beginning to be appreciated. Less is known about whether A2B receptor activation is protective during ischemia-reperfusion in part due to the unavailability of selective and potent A2B antagonists. Harnessing the specificity of gene-knockout models and combining it with a traditional receptor-ligand approach, it is now possible to distinctly isolate the protective contribution of each of these receptor subtypes during ischemia-reperfusion using two lines of mice with targeted deletion of either A2A or A2B receptors. The specific aims are: 1) Characterize the effects of ischemia-reperfusion in isolated hearts from adenosine A2A and A2B receptor knockout mice, 2) Develop an in vivo model of regional myocardial ischemia-reperfusion in adenosine A2A and A2B receptor knockout mice, and 3) Examine the subcellular signaling mechanisms involved in protection from ischemia-reperfusion in adenosine A2A and A2B receptor knockout mice.

描述（由申请人提供）： 该提案的主要目的是将主要研究者发展成为心血管疾病领域的独立临床科学家。申请人是一名儿科重症监护医生，积极参与基础科学研究，尽管离开临床职责的时间有限（35%）。如果获得资助，该奖项将允许75%的时间用于研究培训和追求特定的科学目标。在一位公认的腺苷药理学家的赞助下，该提案包括研究生水平课程的课程设置、定期安排的科学研讨会、参加国家会议、科学技术培训以及进一步参与指导研究生。在一所大学医学院的充分支持下，一个由知名科学家和临床科学家组成的多学科咨询委员会将指导主要研究者的职业发展。这项研究将探讨腺苷A2 A和A2 B受体在心肌缺血再灌注耐受中的相对作用。腺苷是代谢供需失衡时释放的一种“报复性代谢物”，通过激活至少四种不同的受体亚型发挥心脏保护作用。阐明每种腺苷受体亚型对缺血-再灌注反应的贡献仍然是开发用于心脏病临床管理的潜在药理学疗法的重要步骤。虽然A2 A受体主要负责调节冠状动脉血流，但它们对缺血-再灌注保护的作用才刚刚开始被认识。关于A2 B受体激活在缺血再灌注期间是否具有保护作用的部分原因是由于选择性和有效的A2 B拮抗剂的不可用性，目前知之甚少。利用基因敲除模型的特异性并将其与传统的受体-配体方法相结合，现在可以使用两种靶向缺失A2 A或A2 B受体的小鼠系在缺血-再灌注期间清楚地分离这些受体亚型中的每一种的保护作用。具体目标是：1）表征腺苷A2 A和A2 B受体敲除小鼠的离体心脏中的缺血-再灌注效应，2）在腺苷A2 A和A2 B受体敲除小鼠中建立局部心肌缺血-再灌注的体内模型，和3）检查腺苷A2 A和A2 B受体敲除小鼠中参与缺血-再灌注保护的亚细胞信号传导机制。