Adenosine Receptors and Atherogenesis

腺苷受体和动脉粥样硬化形成

• 批准号: 8035319
• 负责人: KATYA RAVID
• 金额: $ 40.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035319
• 关键词: Ablation; Address; Adenosine; Adenylate Cyclase; Adhesions; Affect; Affinity; Age; Apolipoprotein E; Atherosclerosis; Attention; Balloon Angioplasty; Binding; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CXCR4 gene; Cells; Coronary; Data; Development; Diet; Fatty acid glycerol esters; Functional disorder; Gelatinase B; Gene Activation; Gene Deletion; Gene Expression; Gene Expression Regulation; Genes; Health; Homeostasis; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemia; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Lesion; Leukocytes; Ligands; Light; Mediating; Messenger RNA; Metalloproteases; Mus; Nuclear; Pathogenesis; Pathology; Phenotype; Play; Process; Production; Proteins; Purinergic P1 Receptors; Receptor Activation; Receptor Gene; Regulation; Relative (related person); Reporter Genes; Reporting; Research; Research Proposals; Role; Signal Transduction; Smooth Muscle Myocytes; Stress; Stromal Cell-Derived Factor 1; TNF gene; Therapeutic Agents; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Diseases; Vasodilation; Western World; atherogenesis; cell motility; cytokine; femoral artery; in vivo; inhibitor/antagonist; injured; macrophage; mouse model; novel; progenitor; promoter; receptor; research study; response; response to injury; restenosis; sex; therapeutic target; tool; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Adenosine binding to adenylyl cyclase stimulatory (A2-type) adenosine receptors (ARs) induces coronary vasodilatation, inhibits human aortic vascular smooth muscle cell proliferation, and affects arterial wall matrix production, all of which are important components of atherosclerosis/restenosis. The role of the low affinity A2bARs in regulating vascular pathology in vivo had not been examined prior to our study. To further address this, we generated the first A2bAR-knockout (KO)/reporter gene-knock-in mouse model and showed reported gene expression primarily in VSMC and macrophages, in accordance with the endogenous profile in control mice. Augmentation of proinflammatory cytokines, such as tumor necrosis factor-1 (TNF-1), is the underlying mechanism for an observed upregulation of leukocyte adhesion in the vasculature of these A2bAR KO mice, as compared with age-, sex-, and strain-matched control mice. On the other hand, the A2bAR gene receptor, itself, is induced by TNF-1, suggesting a regulatory loop. A2bAR KO mice display greater lesion formation after guidewire-induced femoral artery injury. This occurs in association with the upregulation of CXCR4, a protein known to promote mobilization of progenitors and inflammatory cells to the vessel by interaction with its ligand stromal cell-derived factor-1 (SDF-1). Furthermore, bone marrow (BM) transplantation experiments indicate that the inflammatory response and vascular lesion formation are significantly regulated by BM-derived A2bARs. Building upon these novel findings, we hypothesize that A2bAR-mediated signaling regulates the expression of CXRC4 and, hence, plays a vital role in vascular lesion formation. It is our contention that macrophage A2bARs, via their ability to control the level of inflammatory cytokines, are capable of significantly protecting against vascular pathology on their own, consistent with the BM transplantation experiments. Finally, identifying mechanisms of A2bAR gene regulation by TNF-1 should lead the way for the development of strategies for controlling vascular dysfunction during inflammation. Three specific aims of research are proposed: Aim 1. To examine the direct participation of BM cells and/or their signals in mediating effects of the A2bAR on lesion formation during vascular injury and atherosclerosis, and to study related mechanisms, with a focus on the contribution of macrophage A2bARs. Aim 2. To elucidate the mechanism of control of the CXCR4/SDF-1 axis by the A2bAR. Aim 3. To study the mechanism of A2bAR gene activation by TNF-1 in primary cultures and in vivo. Taken together, our proposed investigations should shed new light on the role of A2bARs in the pathogenesis of vascular dysfunction, and could focus attention on A2bAR activation as a therapeutic target. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a leading cause of vascular disease in the Western world. Our research proposal builds upon novel findings, including the identification of the A2b adenosine receptor as protective against atherosclerosis/restenosis. The mechanisms leading to this protection and the control of expression of this receptor gene are the focus of research in this proposal.

描述（由申请人提供）：腺苷与腺苷酸环化酶刺激性（A2型）腺苷受体（ARS）诱导冠状动脉血管舒张作用，抑制人类主动脉血管平滑肌细胞的增殖，并影响动脉壁的生产，其所有是重要组成术的组合综合综合的动脉壁成分。在我们的研究之前，尚未检查低亲和力A2BAR在调节体内血管病理学中的作用。为了进一步解决这一问题，我们根据对照小鼠中的内源性谱，生成了第一个A2BAR-KNOCKOUT（KO）/报告基因基因敲入小鼠模型。与年龄，性，性别匹配的对照小鼠相比，这些A2BAR KO小鼠的脉管系统中观察到白细胞粘附上调上调的基础机制，例如观察到白细胞粘附上调上调白细胞粘附的基础机制。另一方面，TNF-1诱导A2BAR基因受体本身，提示调节环。 A2BAR KO小鼠在导丝引起的股动脉损伤后表现出更大的病变形成。这与CXCR4的上调有关，CXCR4是一种已知蛋白质，通过与其配体基质细胞衍生的因子1（SDF-1）相互作用，已知促进祖细胞和炎症细胞向血管动员的蛋白质。此外，骨髓（BM）移植实验表明，炎症反应和血管病变形成受BM衍生的A2BAR的显着调节。在这些新发现的基础上，我们假设A2BAR介导的信号传导调节CXRC4的表达，因此在血管病变形成中起着至关重要的作用。我们的论点是，巨噬细胞A2BAR通过控制炎症细胞因子水平的能力，能够自行显着保护与BM移植实验一致的血管病理。最后，通过TNF-1识别A2BAR基因调节的机制应该为制定炎症过程中控制血管功能障碍的策略带来良好的道路。提出了三个特定的研究目的：目标1。检查BM细胞和/或它们的信号在血管损伤和动脉粥样硬化期间对A2BAR对病变形成的介导作用的直接参与，并研究相关机制，重点是巨噬细胞A2BAR的贡献。目标2。阐明A2BAR控制CXCR4/SDF-1轴的机理。目的3。研究TNF-1在原发性培养物和体内的A2BAR基因激活的机制。综上所述，我们提出的研究应该对A2BAR在血管功能障碍发病机理中的作用进行新的启示，并可以将注意力集中在A2BAR激活上作为治疗靶点。公共卫生相关性：动脉粥样硬化是西方世界血管疾病的主要原因。我们的研究提案建立在新发现的基础上，包括鉴定A2B腺苷受体以防止动脉粥样硬化/再狭窄。导致这种保护的机制和该受体基因表达的控制是该提案中研究的重点。