Role of Adenosine Receptors in Tissue Protection

腺苷受体在组织保护中的作用

基本信息

批准号：
8387001
负责人：
JOHN A AUCHAMPACH
金额：
$ 37.11万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-18 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8387001
关键词：
ADORA3 gene Acute Acute myocardial infarction Address Adenosine Adenosine A3 Receptor Adverse effects Affinity Agonist Animal Model Anti-Inflammatory Agents Anti-inflammatory Attenuated Binding Sites Biological Preservation Biology Blood Pressure Bone Marrow Cardiac Cardiotonic Agents Cardiovascular system Cause of Death Cells Chemotaxis Chronic Clinical Clinical Trials Collaborations Dendrimers Developed Countries Development Dose Effectiveness Enhancers Genetic Goals Grant Heart Rate Immune system Infarction Inflammation Inflammatory Response Injury Knowledge Lead Left Ventricular Function Left Ventricular Remodeling Ligands Long-Term Effects Mediating Mus Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Netherlands Nodal Nucleosides Organ Outcome Pathogenesis Patients Performance Pharmacotherapy Physiological Process Production Proteins Purine Nucleosides Purinergic P1 Receptors Purines Receptor Activation Reperfusion Injury Reperfusion Therapy Research Research Personnel Ribose Role Series Signal Transduction Structure Superoxides Technology Testing Tissues United States National Institutes of Health Universities Work base design hemodynamics innovation member mouse model neutrophil novel pre-clinical purine receptor recombinase research study response tool

项目摘要

The A3 adenosine receptor (AR) is the most recently identified subtype of receptor for the purine nucleoside adenosine, which remains poorly characterized in terms of its physiological function, particularly in the cardiovascular system. In previous studies, we have demonstrated that administering selective agonists of the A3AR effectively reduces injury in multiple different preclinical animal models of myocardial ischemia and reperfusion. One of the major advantages of A3AR therapy we have observed in our studies is that these agents are effective at doses that exert no adverse hemodynamic effects. The goal of this proposal is to further expand our knowledge of the cardioprotective actions of the A3AR by completing three highly integrated specific aims. In Specific Aim #1, we will extend our ongoing studies to explore potential mechanisms by which A3AR activation provides protection from ischemia/reperfusion injury. Building off of information gained during the previous grant cycle, we will test the hypothesis that A3AR activation attenuates lethal reperfusion injury by suppressing inflammation and neutrophil-mediated tissue injury. This hypothesis will be tested using novel genetic tools allowing for specific deletion of the A3AR in neutrophils in mice. The results of Specific Aim #2 will provide important information that will further explore the translational potential of A3AR agonists for treating ischemic heart disease. We will determine whether or not treating with A3AR agonists post-MI produces long-term preservation in cardiac performance and whether or not A3AR activation directly diminishes maladaptive remodeling responses. The final highly innovative specific aim will test the cardioprotective efficacy of new A3AR ligands that have recently been developed. We will examine the effectiveness of members of a new series of purine agonists with a modified (N)-methanocarba ring structure in place of the ribose, which we have identified as species-independent, highly selective A3AR agonists. The experiments are uniquely designed to examine whether conjugating the compound to a polymeric dendrimer will increase its cardioprotective potency and efficacy by promoting cooperative ligand-receptor interactions. Finally, we will examine the usefulness of allosteric enhancers for the A3AR. These agents act on a distinct binding site of the A3AR protein that increases the affinity of agonists acting at the orthostatic binding site for adenosine. Theoretically, allosteric enhancers offer the opportunity to target diseased tissues where the production of adenosine is increased while avoiding potential side effects caused by activation of receptors in other organs. Overall, the central objective of this proposal is to investigate the pathophysiological role of the A3AR in the cardiovascular and immune systems during myocardial ischemia/reperfusion injury. If our hypotheses are correct, we will demonstrate that A3AR activation reduces lethal reperfusion injury through anti- inflammatory mechanisms and that treating with A3AR agonists will provide, in addition to infarct size reduction, an added benefit to reduce post-infarction maladaptive remodeling. Completing this work will importantly increase our understanding of the basic biology of the A3AR and has the potential to lead to the development of novel new pharmacological strategies for treating patients with ischemic heart disease.

A3 腺苷受体 (AR) 是最近发现的嘌呤核苷受体亚型腺苷的生理功能仍不清楚，特别是在心血管系统。在之前的研究中，我们已经证明，给予选择性激动剂 A3AR 可有效减轻多种不同临床前心肌缺血动物模型的损伤再灌注。我们在研究中观察到的 A3AR 疗法的主要优点之一是，这些药剂在不产生不良血流动力学影响的剂量下是有效的。该提案的目标是通过完成三个高度集成的项目，进一步扩展我们对 A3AR 心脏保护作用的了解具体目标。在具体目标#1中，我们将扩展我们正在进行的研究，通过以下方式探索潜在的机制： A3AR 激活可提供针对缺血/再灌注损伤的保护。根据获得的信息进行构建在上一个资助周期中，我们将测试 A3AR 激活减弱致死性再灌注的假设通过抑制炎症和中性粒细胞介导的组织损伤来损伤。该假设将使用以下方法进行检验新型遗传工具可以特异性删除小鼠中性粒细胞中的 A3AR。具体目标的结果 #2 将提供重要信息，进一步探索 A3AR 激动剂的转化潜力治疗缺血性心脏病。我们将确定是否在 MI 后使用 A3AR 激动剂治疗产生心脏功能的长期保存以及是否直接激活 A3AR 减少适应不良的重塑反应。最终高度创新的具体目标将考验最近开发的新 A3AR 配体的心脏保护功效。我们将检查具有修饰的 (N)-methanocarba 环结构的新系列嘌呤激动剂成员的有效性核糖的位置，我们已将其鉴定为物种独立的、高度选择性的 A3AR 激动剂。这实验经过独特设计，旨在检查化合物是否与聚合树枝状聚合物缀合将通过促进配体-受体的协同相互作用来提高其心脏保护效力和功效。最后，我们将检查变构增强剂对 A3AR 的有用性。这些药物作用于不同的 A3AR 蛋白的结合位点，增加作用于立位结合位点的激动剂的亲和力腺苷。理论上，变构增强剂提供了靶向患病组织的机会，其中腺苷的产生增加，同时避免因受体激活而引起的潜在副作用其他器官。总体而言，该提案的中心目标是研究病理生理学作用心肌缺血/再灌注损伤期间心血管和免疫系统中 A3AR 的作用。如果我们的如果假设是正确的，我们将证明 A3AR 激活通过抗- 炎症机制，并且用 A3AR 激动剂治疗除了减少梗塞面积外，还可以提供另一个好处是减少梗死后适应不良的重塑。完成这项工作将重要增加我们对 A3AR 基础生物学的了解，并有可能引领开发治疗缺血性心脏病患者的新药理学策略。