Role of Adenosine Receptors in Tissue Protection

腺苷受体在组织保护中的作用

• 批准号: 7055253
• 负责人: JOHN A AUCHAMPACH
• 金额: $ 36.98万
• 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/7055253
• 关键词: RNase protection assay; biological signal transduction; cardiac myocytes; cell transplantation; cellular pathology; chemokine; cytokine; cytoprotection; enzyme linked immunosorbent assay; gel mobility shift assay; genetically modified animals; inflammation; laboratory mouse; macrophage; myocardial ischemia /hypoxia; neutrophil; pathologic process; polymerase chain reaction; purinergic receptor; receptor expression; reperfusion; southern blotting; vascular endothelium

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（A3 AR）在心肌细胞中表达，它们调节对缺血应激的反应。此外，A3 AR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A3 AR激动剂提供了深刻的心脏保护，防止心肌缺血/再灌注（I/R）损伤诱导的组织损伤，在小鼠，兔和狗，无论是在缺血前或再灌注时。这项研究计划的目的是了解负责这种组织保护的机制。我们的一般假设是，A3 AR激动剂双重作用于心肌细胞以减少缺血期间的心肌损伤，并作用于骨髓来源的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策略产生具有从心肌细胞选择性缺失的A3 AR基因的同类系小鼠，和2）使用标准移植技术从同类A3 AR基因“敲除”小鼠产生在骨髓衍生细胞中缺乏或表达A3 AR的嵌合小鼠。将使用梗塞的体内小鼠模型和全脑缺血和再灌注的分离的小鼠心脏模型来确定心肌中表达的A3 AR相对于炎性细胞在调节I/R损伤中的相对重要性。提出了另外的研究来研究来自“野生型”、常规A2 AAR基因“敲除”和常规A3 AR基因敲除”小鼠的特定炎症细胞群体中A3 AR的细胞信号传导应答。总的来说，这些研究将联合收割机几个国家的最先进的技术，提供新的明确的信息，细胞特异性机制，A3 AR激活提供保护，从I/R损伤。