Role of Adenosine Receptors in Tissue Protection

腺苷受体在组织保护中的作用

• 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
• 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

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）是最近发现的嘌呤核苷腺苷受体亚型，在其生理功能方面，特别是在心血管系统中，其特征仍然很差。在之前的研究中，我们已经证明，在多种不同的临床前动物心肌缺血和再灌注模型中，给予A3AR选择性激动剂可以有效地减少损伤。我们在研究中观察到的A3AR治疗的主要优点之一是，这些药物在剂量上有效，不会对血流动力学产生不良影响。该提案的目标是通过完成三个高度整合的具体目标，进一步扩大我们对A3AR心脏保护作用的认识。在Specific Aim #1中，我们将扩展我们正在进行的研究，探索A3AR激活对缺血/再灌注损伤提供保护的潜在机制。基于在前一个资助周期中获得的信息，我们将验证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死性再灌注损伤的假设。这一假设将使用新的遗传工具进行测试，允许在小鼠中性粒细胞中特异性删除A3AR。Specific Aim #2的结果将为进一步探索A3AR激动剂治疗缺血性心脏病的转化潜力提供重要信息。我们将确定心肌梗死后使用A3AR激动剂治疗是否能长期维持心脏功能，以及A3AR激活是否能直接减少不适应重构反应。最后一个高度创新的特异性目标将测试最近开发的新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的有效性，这些嘌呤激动剂具有修饰的(N)-甲醇碳环结构来代替核糖，我们已经确定这些嘌呤激动剂是物种独立的，高度选择性的A3AR激动剂。该实验旨在检验将该化合物偶联到聚合树突状分子上是否会通过促进配体-受体的协同相互作用来增加其心脏保护效力和功效。最后，我们将研究变构增强剂对A3AR的有用性。这些药物作用于A3AR蛋白的独特结合位点，从而增加作用于腺苷直立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。总之，本研究的主要目的是研究心肌缺血/再灌注损伤时A3AR在心血管和免疫系统中的病理生理作用。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死性再灌注损伤，并且使用A3AR激动剂治疗除了减少梗死面积外，还可以减少梗死后适应性不良重构。完成这项工作将大大增加我们对A3AR基本生物学的理解，并有可能导致开发新的治疗缺血性心脏病患者的药理策略。