Role of Adenosine Receptors in Tissue Protection

腺苷受体在组织保护中的作用

• 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
• 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

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）是嘌呤核苷受体的最新亚型 腺苷，其特征在其生理功能方面保持较差，尤其是在 心血管系统。在先前的研究中，我们已经证明了管理的选择性激动剂 A3AR有效地减少了多种不同的心肌缺血临床前动物模型和 再灌注。我们在研究中观察到的A3AR治疗的主要优点之一是 药物的剂量无效，不会产生不良血液动力学作用。该提议的目的是 进一步扩大了我们通过完成三个高度整合的A3AR的心脏保护作用的了解 具体目标。在特定目标1中，我们将扩展我们正在进行的研究，以探索潜在的机制 A3AR激活可防止缺血/再灌注损伤。从获得的信息中构建 在上一个赠款周期中，我们将测试A3AR激活减轻致命再灌注的假设 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 新型的遗传工具允许小鼠中性粒细胞中A3AR的特定缺失。特定目标的结果 ＃2将提供重要信息，以进一步探索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 产生心脏性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。最终高度创新的特定目标将测试 最近开发的新A3AR配体的心脏保护功效。我们将检查 具有改性（N） - 甲状腺环结构的新系列嘌呤激动剂的成员的有效性 核糖的位置，我们已经确定为独立于物种的高度选择性A3AR激动剂。这 实验的设计独特，以检查是否将化合物结合到聚合物树枝状聚合物 通过促进配体 - 受体相互作用，将提高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。这些代理商采取了独特的作用 A3AR蛋白的结合位点增加了作用在原位结合位点的激动剂的亲和力 腺苷。从理论上讲，变构增强剂为靶向患病的组织提供了机会 腺苷的产生增加，同时避免受体激活引起的潜在副作用 其他器官。总体而言，该提议的核心目的是研究 心肌缺血/再灌注损伤期间心血管和免疫系统中的A3AR。如果我们 假设是正确的，我们将证明A3AR激活通过抗 - 减少致命的再灌注损伤 炎症机制以及用A3AR激动剂治疗的机制除了梗塞大小降低外，还可以提供 减少病后不良适应性重塑的额外好处。完成这项工作将重要 提高我们对A3AR基本生物学的理解，并有可能导致发展 用于治疗缺血性心脏病患者的新型药理策略。