VLA-4 and VCAM-1 in Advanced Atherosclerosis

VLA-4 和 VCAM-1 在晚期动脉粥样硬化中的作用

• 批准号: 7140037
• 负责人: JOHN Marshall HARLAN
• 金额: $ 24.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140037
• 关键词: T lymphocyte; atherosclerosis; atherosclerotic plaque; cell cell interaction; cell type; extracellular; gene expression; intracellular; laboratory mouse; lead; lipids; macrophage; monocyte; pathologic process; smooth muscle; vascular cell adhesion molecule

There is considerable evidence supporting a causal role for T-lymphocytes, monocytes, and monocytederived macrophages in the initiation, progression, and complications of the atherosclerosis in man as well as in experimental models. Plaque rupture is thought to be the trigger event for acute coronary syndromes in man, and several mouse models of plaque rupture have recently been described. Lesion macrophages in particular have been implicated in plaque rupture by releasing de-stabilizing proteases. Notably, there is evidence for continued recruitment of circulating monocytes into arterial lesions in experimental atherosclerosis, particularly in the rupture-prone shoulder. Moreover, adhesion receptors may also regulate critical functions of emigrated leukocytes resident in lesions, including activation and survival. Thus, the adhesion molecules that mediate monocyte trafficking into the arterial wall a potentially attractive target in advanced as well as early disease.Studies to date of human and experimental lesions suggest a significant role for endothelial VCAM-1 and its major leukocyte counter-receptor VLA-4 (cc4(31) in the early phase of disease, but have not examined the role of VLA-4 or VCAM-1 in the progression of established atherosclerosis or its late complications such as plaque rupture. Since antagonists of VLA-4 have already progressed to clinical trials in other indications, the importance of VLA-4 and VCAM-1 interactions in the progression and late complications of atherosclerosis is a clinically relevant question as patients are most often identified in this stage of the disease. We hypothesize that the VLA-4 and VCAM-1 play important roles in monocyte and T-lymphocyte recruitment to advanced as well as early lesions and that disruption of these adhesion pathways will reduce progression of established lesions and prevent plaque rupture. In order to test this hypothesis, we will utilize a recently developed mouse model in which interferon-induced Cre-loxP-mediated deletion of the ot4 gene can be achieved at any time post-natal. These a4-deleted animals will be studied in both the ApoE-/- (Aim 1) and LDRL-/- (Aim 2) background, allowing us to define for the first time the contribution of VLA-4 in the progression of established lesions and plaque rupture as well as in lesion initiation. To complement the VLA-4 studies, we will also examine the role of VCAM-1 in lesion initiation/progression in a model of conditional knockout of endothelial VCAM-1 (Aim 3).

有大量证据支持T淋巴细胞，单核细胞和单核细胞的因果作用 人类动脉粥样硬化的开始，进展和并发症的巨噬细胞 以及在实验模型中。斑块破裂被认为是急性冠状动脉的触发事件 最近已经描述了人类中的综合征和几种斑块破裂的小鼠模型。病变 特别是巨噬细胞通过释放稳定的蛋白酶而与斑块破裂有关。 值得注意的是，有证据表明继续募集循环单核细胞中的动脉病变 实验性动脉粥样硬化，特别是在易发的肩部。此外，粘附受体 还可能调节居住在病变中的移民白细胞的关键功能，包括激活和 生存。因此，介导单核细胞运输到动脉壁的粘附分子可能有可能 在晚期和早期疾病中有吸引力的靶标。 暗示内皮VCAM-1及其主要白细胞反受体VLA-4的重要作用（CC4（31） 在疾病的早期阶段，但尚未检查VLA-4或VCAM-1在进展中的作用 建立了动脉粥样硬化或其晚期并发症，例如斑块破裂。由于VLA-4的拮抗剂 在其他指示下，已经发展到临床试验，VLA-4和VCAM-1的重要性 动脉粥样硬化的进展和晚期并发症的相互作用是一个临床上相关的问题 在疾病的这个阶段，最常发现患者。 我们假设VLA-4和VCAM-1在单核细胞和T淋巴细胞中起重要作用 招募高级和早期病变以及这些粘附途径的破坏将会 减少已建立病变的进展并防止牙菌斑破裂。为了检验这一假设，我们 将利用最近开发的小鼠模型，其中干扰素诱导的Cre-loxp介导的删除 ot4基因可以在产后的任何时候实现。这些A4删除的动物将在两者中研究 apoe - / - （AIM 1）和LDRL - / - （AIM 2）背景，使我们能够首次定义 VLA-4在已建立的病变和​​斑块破裂以及病变启动中的进展中。到 补充VLA-4研究，我们还将研究VCAM-1在病变开始/进展中的作用 内皮VCAM-1的条件敲除模型（AIM 3）。