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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：
8588955
负责人：
JOHN A AUCHAMPACH
金额：
$ 36.83万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8588955
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）是最近鉴定的嘌呤核苷受体亚型腺苷，其在生理功能方面的特征仍然很差，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， A3 AR有效地减少了心肌缺血的多种不同临床前动物模型中的损伤，再灌注我们在研究中观察到的A3 AR疗法的主要优点之一是，药剂在不产生不利的血液动力学作用的剂量下是有效的。本提案的目的是通过完成三个高度集成的A3 AR，进一步扩展我们对A3 AR心脏保护作用的了解明确的目标。在具体目标#1中，我们将通过以下方式扩展我们正在进行的研究，以探索潜在的机制：其中A3 AR激活提供了对缺血/再灌注损伤的保护。根据获得的信息在上一个资助周期中，我们将检验A3 AR激活减弱致死性再灌注的假设通过抑制炎症和嗜酸性粒细胞介导的组织损伤来治疗损伤。该假设将通过以下方式进行检验：新的遗传工具允许在小鼠中性粒细胞中特异性缺失A3 AR。具体目标的结果 #2将提供重要信息，进一步探索A3 AR激动剂的翻译潜力，治疗缺血性心脏病。我们将确定是否在MI后使用A3 AR激动剂治疗产生心脏性能的长期保存以及A3 AR是否直接激活减少适应不良的重塑反应。最后一个高度创新的具体目标将考验最近开发的新A3 AR配体的心脏保护功效。我们会研究具有修饰的（N）-甲烷碳环结构的新系列嘌呤激动剂的成员在核糖的位置，我们已经确定为物种独立的，高选择性的A3 AR激动剂。的实验被独特地设计以检查是否将化合物缀合到聚合物树枝状聚合物上将通过促进协同配体-受体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A3 AR的有用性。这些代理人对一个独特的行为 A3 AR蛋白的结合位点，其增加作用于直立结合位点的激动剂对腺苷。从理论上讲，变构增强剂提供了靶向病变组织的机会，腺苷的产生增加，同时避免了由受体激活引起的潜在副作用，其他器官。总的来说，这项建议的中心目标是研究的病理生理作用，心肌缺血/再灌注损伤时心血管和免疫系统中的A3 AR如果我们的假设是正确的，我们将证明A3 AR激活通过抗- 炎症机制，并且用A3 AR激动剂治疗，除了梗死面积减小，减少梗死后适应不良重塑的额外益处。完成这项工作将非常重要。增加我们对A3 AR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型药理学策略。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A(3) adenosine receptor activation during reperfusion reduces infarct size through actions on bone marrow-derived cells.

DOI：
10.1016/j.yjmcc.2010.01.018
发表时间：
2010-08
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Ge ZD;van der Hoeven D;Maas JE;Wan TC;Auchampach JA
通讯作者：
Auchampach JA

Extended N(6) substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor.

刚性 C2-芳基乙炔基核苷的扩展 N(6) 取代，用于探索细胞外环在 A3 腺苷受体配体识别中的作用。

DOI：
10.1016/j.bmcl.2014.06.006
发表时间：
2014
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Tosh,DilipK;Paoletta,Silvia;Chen,Zhoumou;Moss,StevenM;Gao,Zhan-Guo;Salvemini,Daniela;Jacobson,KennethA
通讯作者：
Jacobson,KennethA

Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists.

DOI：
10.1021/acs.jmedchem.5b01998
发表时间：
2016-04-14
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Tosh DK;Ciancetta A;Warnick E;O'Connor R;Chen Z;Gizewski E;Crane S;Gao ZG;Auchampach JA;Salvemini D;Jacobson KA
通讯作者：
Jacobson KA

Structural probing of off-target G protein-coupled receptor activities within a series of adenosine/adenine congeners.