Role of Adenosine Receptors in Tissue Protection

腺苷受体在组织保护中的作用

• 批准号: 7388215
• 负责人: JOHN A AUCHAMPACH
• 金额: $ 35.91万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388215
• 关键词: Adenosine; Adenosine A3 Receptor; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Arts; Bone Marrow; Canis familiaris; Cardiac; Cardiac Myocytes; Cells; Clinical; Disease; Endothelial Cells; Genes; Genetic; Goals; Heart; Immune; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Knock-out; Knockout Mice; Mediating; Modeling; Mus; Myocardial; Myocardial Ischemia; Myocardium; Oryctolagus cuniculus; Pathogenesis; Physiological reperfusion; Population; Purinergic P1 Receptors; Receptor Gene; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Research Proposals; Role; Signal Transduction; Standards of Weights and Measures; Stress; Techniques; Time; Tissues; Transplantation; adenosine receptor activation; autocrine; chemokine; congenic; cytokine; in vivo; macrophage; mouse model; neutrophil; paracrine; receptor; response

DESCRIPTION (provided by applicant): Current evidence suggests that A3 adenosine receptors (A3ARs) are expressed in cardiac myocytes, where they regulate responses to ischemic stress. In addition, A3ARs are expressed in cells involved in the inflammatory response including neutrophils, macrophages, and endothelial cells. In these cells, they mediate anti-inflammatory actions. In preliminary studies, we have shown that newly developed A3AR agonists provide profound cardiac protection against tissue damage induced by myocardial ischemia/reperfusion (I/R) injury in mice, rabbits, and dogs whether they are given prior to ischemia or at the time of reperfusion. The goal of this research proposal is to understand the mechanisms responsible for this tissue protection. Our general hypothesis is that A3AR agonists act dually on cardiac myocytes to reduce myocardial injury during ischemia, and act on bone marrow-derived cells to reduce inflammation during reperfusion. The studies involve the use of genetic approaches to: 1) produce a congenic line of mice with the A3AR gene selectively deleted from cardiomyocytes using the Cre/LoxP strategy, and 2) to produce from congenic A3AR gene "knock-out" mice, chimeric mice lacking or expressing the A3AR in bone marrow-derived cells using standard transplantation techniques. An in vivo mouse model of infarction and an isolated mouse heart model of global ischemia and reperfusion will be used to determine the relative importance of A3ARs expressed in the myocardium versus inflammatory cells in regulating I/R injury. Additional studies are proposed to study cellular signaling responses of A3ARs in specific populations of inflammatory cells from "wild-type", conventional A2AAR gene "knock-out", and conventional A3AR gene knock-out" mice. Collectively, these studies will combine several state-of-the-art techniques to provide new definitive information on the cell-specific mechanisms by which A3AR activation provides protection from I/R injury.

描述（由申请人提供）：目前的证据表明，A3 腺苷受体 (A3AR) 在心肌细胞中表达，调节对缺血应激的反应。此外，A3AR 在参与炎症反应的细胞中表达，包括中性粒细胞、巨噬细胞和内皮细胞。在这些细胞中，它们介导抗炎作用。在初步研究中，我们已经表明，新开发的 A3AR 激动剂可以对小鼠、兔和狗的心肌缺血/再灌注 (I/R) 损伤引起的组织损伤提供深刻的心脏保护，无论是在缺血之前还是在缺血时给予。再灌注。这项研究计划的目标是了解负责这种组织保护的机制。我们的一般假设是，A3AR激动剂双重作用于心肌细胞以减少缺血期间的心肌损伤，并作用于骨髓源性细胞以减少再灌注期间的炎症。这些研究涉及使用遗传方法：1）使用 Cre/LoxP 策略产生从心肌细胞选择性删除 A3AR 基因的同源小鼠系，以及 2）从同源 A3AR 基因“敲除”小鼠中产生嵌合体使用标准移植技术在骨髓来源细胞中缺乏或表达 A3AR 的小鼠。体内梗死小鼠模型和整体缺血和再灌注的离体小鼠心脏模型将用于确定心肌中表达的 A3AR 与炎症细胞在调节 I/R 损伤中的相对重要性。还提出了其他研究来研究来自“野生型”、传统 A2AAR 基因“敲除”和传统 A3AR 基因敲除小鼠的特定炎症细胞群中 A3AR 的细胞信号反应。总的来说，这些研究将结合几项研究最先进的技术提供有关细胞特异性机制的新的明确信息，A3AR 激活通过该机制提供免受 I/R 损伤的保护。