RAGE and Mechanisms of Accelerated Atherosclerosis

RAGE 与加速动脉粥样硬化的机制

• 批准号: 6950146
• 负责人: ANN MARIE SCHMIDT
• 金额: $ 14万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950146
• 关键词: atherosclerosis; atherosclerotic plaque; biological signal transduction; blood lipoprotein metabolism; cell motility; diabetes mellitus; disease /disorder model; gene expression; genetically modified animals; glycation; hyperglycemia; hyperlipidemia; inflammation; insulin sensitivity /resistance; intermolecular interaction; laboratory mouse; molecular pathology; pathologic process; phagocytes; receptor; receptor binding; transport proteins; vascular endothelium; vascular smooth muscle

The striking increase in atherosclerosis in diabetes suggests that factors directly consequent to hyperglycemia impact on the response of the blood vessel wall to superimposed biochemical and metabolic stresses, such as hyperlipidemia. Sustained vascular accumulation of ligands for Receptor for AGE (RAGE), the products of nonenzymatic glycation and oxidation of proteins/lipids, the Advanced Glycation Endproducts (AGEs); and S100/calgranulins; a family of proinflammatory cytokines, provides one such mechanism for acceleration of diabetic atherosclerosis. Pharmacological blockade of RAGE, or transgenic mice in whom RAGE signalling is disabled, secondary to cell-specific introduction of a transgene in which the cytosolic tail is deleted, suppressed acceleration of diabetic atherosclerosis in mice deficient in apolipoprotein (ape) E (0). Nondiabetic homozygous RAGE (0) mice in the ape E (0) background displayed decreased atherosclerosis compared to mice solely deficient in ape E (0). Substantial progress in the first years of the Program Project has been made in identifying the signal transduction cascades recruited by ligand engagement of RAGE. Recent studies in a yeast two-hybrid assay indicated that the cytosolic domain of RAGE interacts with a newly-identified member of the diaphanous family of proteins. Diaphanous molecules, first identified in Drosophila, are critical intracellular "bridges" of cell signalling and modulation of the actin cytoskeleton in mammalian cells, as specific domains of these molecules engage effectors such as the Rho GTPases, thereby impacting on downstream cascades, such as Nuclear Factor (NF)-kB; and polypeptides linked to cellular motility. We hypothesize that RAGE-dependent mechanisms trigger activation of signalling pathways linked to vascular inflammation and cellular motility. Here, we propose to rigorously test the role of RAGE in atherosclerosis using RAGE (0) mice and transgenic mice in whom RAGE signalling is disabled in endothelial cells, smooth muscle cells and cells of mononuclear phagocyte lineage, and to determine the critical domains of RAGE and diaphanous-like protein that mediate their interactions, and, thereby, modulation of cellular motility and signalling. These studies will further our understanding of mechanisms by which RAGE activation is linked to vascular stress, and highlight the impact of this pathway for future therapeutic strategies in atherosclerosis. This Project is closely linked to Project by Yan, as each studies RAGE-dependent vascular stress. This Project shares mouse models and ligand-RAGE reagents with each of the other projects. This Project will utilize all three Cores of the Program Project.

糖尿病动脉粥样硬化的显着增加表明，直接导致高血糖的因素会影响血管壁对叠加生化和代谢胁迫（例如高脂血症）的反应。 配体的持续血管积累，用于年龄的受体（RAGE），非酶糖化和蛋白质/脂质的氧化产物，晚期糖基化末端产物（年龄）；和s100/calgranulins;促炎细胞因子家族提供了一种加速糖尿病动脉粥样硬化的机制。愤怒的药理学阻滞或残疾的愤怒信号传导的转基因小鼠，其次是细胞特异性引入转基因的转基因，其中胞质尾巴被删除，抑制了载脂蛋白（APE）E（0）的小鼠糖尿病性动脉粥样硬化加速。与仅缺乏APE E（0）的小鼠相比，APE E（0）背景中的非糖尿病纯合愤怒（0）小鼠降低了动脉粥样硬化。在该计划项目的头几年中，已经取得了重大进展，以确定配体的愤怒参与招募的信号转导级联。酵母两杂交测定法的最新研究表明，愤怒的胞质结构域与diaphanous蛋白质的新识别成员相互作用。 drosophila最初鉴定出的腹膜分子是哺乳动物细胞中细胞信号传导的关键细胞内“桥”和肌动蛋白细胞骨架的调节，因为这些分子的特定域与Rho GTPase等效应子相关，从而影响了诸如下游级别的核心因素（例如核因子（例如NF））-KB（NF）-KB；和与细胞运动有关的多肽。 我们假设依赖愤怒的机制会触发与血管炎症和细胞运动有关的信号通路的激活。 在这里，我们建议使用愤怒（0）小鼠和转基因小鼠严格测试愤怒在动脉粥样硬化中的作用，在内皮细胞中，愤怒信号传导在内皮细胞，平滑肌细胞和单核吞噬细胞谱系的细胞中被残障，并确定愤怒的蛋白质的关键蛋白质，并在其中介导了它们的相互作用，并在此中介导了它们，并在此中介导了它们，并使其对其进行了调解，并使其对其进行了调解，并确定了这些蛋白质。这些研究将进一步了解我们对机制的理解 愤怒的激活与血管应激有关，并强调了该途径对动脉粥样硬化对未来治疗策略的影响。随着每个研究依赖于依赖的血管压力，该项目与YAN的项目紧密相关。该项目与其他每个项目共享鼠标模型和配体式试剂。该项目将利用程序项目的所有三个内核。