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Ischemia-Reperfusion in A2A and A2B Knockout Hearts

A2A 和 A2B 敲除心脏的缺血再灌注

基本信息

批准号：
7256490
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
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7256490
关键词：
Acetates Adenosine Adenosine A2B Receptor Adenosine A3 Receptor Adrenergic Antagonists Adverse effects Advisory Committees Anterior Descending Coronary Artery Award Azathioprine Basic Science Cardiac Cardiac Myocytes Cardiovascular Diseases Childhood Clinical Clinical Management Coronary Critical Care Development Educational Curriculum Endothelium Funding Heart Heart Diseases Hour In Vitro Infarction Injury Ischemia Knock-out Knockout Mice Lactate Dehydrogenase Lactate Dehydrogenases Left Ligands Measurement Measures Mediating Mentors Metabolic Modeling Mus Myocardial Myocardial Ischemia Operative Surgical Procedures Personal Satisfaction Phorbol Phorbols Physicians Physiological reperfusion Pinacidil Potassium Principal Investigator Protein Kinase C Protein Kinase C Inhibitor Purinergic P1 Receptors Receptor Activation Recovery Regulation Relative (related person)Reperfusion Injury Reperfusion Therapy Research Research Training Risk Role Schedule Scientist Signal Transduction Specificity Students Techniques Time Training Universities Ventricular base career chelerythrine chronotropic in vivo Model inhibitor/antagonist knockout gene medical schools multidisciplinary pressure receptor response size

项目摘要

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）：