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来源的巨噬细胞在人类和实验模型动脉粥样硬化的发生、发展和并发症中起因果作用。斑块破裂被认为是人类急性冠脉综合征的触发事件，最近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不稳定的蛋白水解酶参与斑块破裂。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，特别是在易破裂的肩部。此外，黏附受体还可能调节驻留在病变中的移行白细胞的关键功能，包括激活和存活。因此，介导单核细胞进入动脉壁的黏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。到目前为止，对人类和实验性病变的研究表明，内皮细胞VCAM-1及其主要的白细胞对抗性受体VLA-4a4B1在疾病的早期阶段具有重要作用，但尚未研究VLA-4或VCAM-1在已建立的动脉粥样硬化或其晚期并发症(如斑块破裂)的进展中的作用。由于VLA-4的拮抗剂已经在其他适应症上进行了临床试验，VLA-4和VCAM-1的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一个临床相关的问题，因为患者通常在疾病的这个阶段被发现。我们假设VLA-4和VCAM-1在晚期和早期病变的单核细胞和T淋巴细胞募集中发挥重要作用，破坏这些黏附通路将减少已建立的病变的进展试验，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。这些(4-缺失)动物将在ApoE-/-(目标1)和LDRL-/-(目标2)背景下进行研究，使我们能够首次确定VLA-4在已建立的病变和斑块破裂的进展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VCAM-1条件性敲除的模型(目标3)中检查VCAM-1在病变启动/进展中的作用。

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).