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：
8040564
负责人：
JOHN A AUCHAMPACH
金额：
$ 39.49万
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/8040564
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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Ischemic heart disease is the leading cause of death in the U.S. and other industrialized nations. This research will potentially lead to the development of new drug therapies for treating patients with acute myocardial infarction. This research will also increase our understanding of the biology of adenosine and its receptors in the cardiovascular and immune systems.

描述（由申请人提供）：A3腺苷受体（AR）是最近鉴定的嘌呤核苷腺苷受体亚型，其生理功能（特别是在心血管系统中）的特征仍然很少。在之前的研究中，我们已经证明，在多种不同的临床前心肌缺血和再灌注动物模型中，施用选择性A3AR激动剂可以有效减少损伤。我们在研究中观察到的 A3AR 疗法的主要优点之一是，这些药物在剂量下有效，不会产生不良的血流动力学影响。该提案的目标是通过完成三个高度集成的具体目标，进一步扩大我们对 A3AR 心脏保护作用的了解。在具体目标#1中，我们将扩展正在进行的研究，探索 A3AR 激活提供缺血/再灌注损伤保护的潜在机制。根据之前资助周期中获得的信息，我们将检验以下假设：A3AR 激活通过抑制炎症和中性粒细胞介导的组织损伤来减轻致命性再灌注损伤。这一假设将使用新型遗传工具进行测试，该工具可以特异性删除小鼠中性粒细胞中的 A3AR。具体目标#2 的结果将提供重要信息，进一步探索 A3AR 激动剂治疗缺血性心脏病的转化潜力。我们将确定 MI 后使用 A3AR 激动剂治疗是否能长期保持心脏功能，以及 A3AR 激活是否直接减少适应不良的重塑反应。最终高度创新的具体目标将测试最近开发的新型 A3AR 配体的心脏保护功效。我们将研究一系列新的嘌呤激动剂成员的有效性，这些嘌呤激动剂具有修饰的 (N)-methanocarba 环结构代替核糖，我们已将其鉴定为物种独立的、高度选择性的 A3AR 激动剂。这些实验的独特设计是为了检查该化合物与聚合树枝状聚合物的缀合是否会通过促进配体-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 A3AR 蛋白的独特结合位点，增加作用于腺苷立位结合位点的激动剂的亲和力。理论上，变构增强剂提供了靶向病变组织的机会，其中腺苷的产生增加，同时避免了其他器官中受体激活引起的潜在副作用。总体而言，该提案的中心目标是研究心肌缺血/再灌注损伤期间 A3AR 在心血管和免疫系统中的病理生理学作用。如果我们的假设是正确的，我们将证明A3AR激活通过抗炎机制减少致命性再灌注损伤，并且用A3AR激动剂治疗除了减少梗塞面积外，还将提供减少梗塞后适应不良重塑的额外益处。完成这项工作将重要地增加我们对 A3AR 基础生物学的理解，并有可能导致开发治疗缺血性心脏病患者的新药理学策略。公共卫生相关性：缺血性心脏病是美国和其他工业化国家的主要原因。这项研究将有可能促进治疗急性心肌梗死患者的新药物疗法的开发。这项研究还将增进我们对腺苷及其在心血管和免疫系统中的受体的生物学的了解。