Role of Adenosine Receptors in Tissue Protection

腺苷受体在组织保护中的作用

• 批准号: 6922340
• 负责人: JOHN A AUCHAMPACH
• 金额: $ 37.88万
• 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/6922340
• 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）：当前的证据表明A3腺苷受体（A3AR）在心肌细胞中表达，它们调节对缺血性压力的反应。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激动剂可为小鼠，兔子和狗在缺血和狗中造成的心肌缺血/再灌注（I/R）损伤引起的组织损伤提供深刻的心脏保护。该研究建议的目的是了解负责该组织保护的机制。我们的总体假设是，A3AR激动剂在心肌细胞上进行双重作用，以减少缺血期间心肌损伤，并作用于骨髓来源的细胞，以减少再灌注过程中的炎症。该研究涉及使用遗传学方法：1）使用CRE/LOXP策略从心肌细胞中选择性删除的A3AR基因以及2）产生一个a3AR基因，而2）用chimeric小鼠，嵌合小鼠使用A3AR在骨骼元素中缺乏或表达A3AR的Transplant transaltation transeike croman a3AR基因“敲除型”小鼠，使用嵌合小鼠。体内梗塞的体内小鼠模型和全局缺血和再灌注的孤立小鼠心脏模型将用于确定在心肌与炎症细胞中在调节I/R损伤中表达的A3AR的相对重要性。 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.