VLA-4 And VCAM-1 in Advanced Atherosclerosis

描述（由申请人提供）：有相当多的证据支持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动脉粥样硬化的发生、进展和并发症中的因果作用。斑块破裂被认为是人类急性冠状动脉综合征的触发事件，最近有几种小鼠斑块破裂模型被描述。病变巨噬细胞通过释放去稳定化蛋白酶参与斑块破裂。值得注意的是，有证据表明，在实验性动脉粥样硬化中，循环单核细胞持续募集到动脉病变中，特别是在容易破裂的肩部。此外，粘附受体也可能调节病变中迁移白细胞的关键功能，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都是一个潜在的有吸引力的靶点。迄今为止，对人类和实验病变的研究表明，内皮细胞VCAM-1及其主要的白细胞对抗受体vcam -4 （a4B1）在疾病早期阶段具有重要作用，但尚未研究VCAM-1或VCAM-1在已建立的动脉粥样硬化的进展或其晚期并发症（如斑块破裂）中的作用。由于vca -4拮抗剂已经在其他适应症中进行了临床试验，因此vca -4和VCAM-1相互作用在动脉粥样硬化进展和晚期并发症中的重要性是一个与临床相关的问题，因为患者通常在该疾病阶段被发现。我们假设vca -4和VCAM-1在单核细胞和t淋巴细胞募集到晚期和早期病变中发挥重要作用，并且这些粘附途径的破坏将减少已建立病变的进展试验并防止斑块破裂。为了验证这一假设，我们将利用最近开发的小鼠模型，在该模型中，干扰素诱导的cre - loxp介导的(4)基因缺失可以在出生后的任何时间实现。我们将在ApoE-/- (Aim 1)和LDRL-/- (Aim 2)背景下研究这些（4缺失）的动物，从而首次确定VLA-4在已建立的病变进展、斑块破裂以及病变起始中的作用。为了补充VLA- 4的研究，我们还将在内皮细胞条件敲除VCAM-1的模型中研究VCAM-1在病变发生/进展中的作用（目的3）。

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).