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: 6858453
• 负责人: JOHN Marshall HARLAN
• 金额: $ 37.9万
• 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: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858453
• 关键词: T lymphocyte; atherosclerosis; atherosclerotic plaque; flow cytometry; gene deletion mutation; gene expression; genetically modified animals; immunocytochemistry; integrins; laboratory mouse; monocyte; polymerase chain reaction; vascular cell adhesion molecule

DESCRIPTION (provided by applicant): There is considerable evidence supporting a causal role for T- lymphocytes, monocytes, and monocyte-derived 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 a4B1) 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 test this 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 (4 gene can be achieved at any time post-natal. These (4-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).

描述（由申请人提供）：有大量证据支持T-淋巴细胞，单核细胞和单核细胞衍生的巨噬细胞在人类和实验模型中的动脉粥样硬化的起始，进展和并发症中的因果关系。牙菌斑破裂被认为是人类急性冠状动脉综合征的触发事件，最近已经描述了几种斑块破裂的小鼠模型。尤其是病变巨噬细胞通过释放稳定蛋白酶而与牙菌斑破裂有关。值得注意的是，有证据表明，在实验性动脉粥样硬化中，尤其是在易发的肩膀上，持续募集循环单核细胞为动脉病变。此外，粘附受体还可以调节居住在病变中的移民白细胞的关键功能，包括激活和存活。因此，介导单核细胞运输到动脉壁的粘附分子在晚期和早期疾病中具有有吸引力的靶标。迄今为止人类和实验性病变的研究表明，在疾病的早期阶段，内皮VCAM-1及其主要的白细胞反受体VLA-4 A4B1及其主要作用，但没有检查VLA-4或VCAM-1在既定的动脉粥样硬化或其后期并发症或其后期并发症（例如pla）的作用。由于VLA-4的拮抗剂已经在其他适应症中发展为临床试验，因此VLA-4和VCAM-1相互作用在动脉粥样硬化的进展和晚期并发症中的重要性是临床上相关的问题，因为患者在该疾病的这一阶段最常见。我们假设VLA-4和VCAM-1在单核细胞和T淋巴细胞募集到高级病变和早期病变中起重要作用，并且这些粘附途径的破坏将减少既定病变的进展，并预防斑块破裂。为了检验这一假设，我们将利用一个最近开发的鼠标模型，其中干扰素诱导的cre-loxP介导的缺失（可以在产发后的任何时候实现4个基因。这些基因都可以在产后进行。这些动物将在APOE-/ - / - （AIM 1）和LDRL - / - （AIM 2）的贡献中，在APOE-/ - / - （aim 2）中进行贡献，以供您进行贡献。已建立的病变和​​斑块破裂以及在病变开始中。