CELL SURVIVAL PATHWAYS

纤维帽的破裂是导致 晚期患者管腔表面血栓栓塞症并发症 动脉粥样硬化斑块。为斑块奠定基础的因素 破坏包括进行性帽子萎缩伴细胞丢失和 矩阵。不幸的是，这些信念很难检验，因为缺乏 动物模型。我们建议通过以下方式解决这个问题 结合人体组织和动物模型的跨学科方法 对可能支持这一过程的分子途径的研究。在……里面 Grant 1(T.Hatsukami和C.袁)，我们将使用高分辨率进行研究 磁共振成像，一组中度内窥镜下的患者 颈动脉狭窄。我们将检验这样一种假设，即纤维 这些病变的帽状结构通常较厚，帽状结构变薄 在斑块扩大和管腔缩小后发展。我们还将 确定缺血性神经事件或斑块破裂 通过切除斑块的组织学评估来评估与 纤维帽变薄。在《授予2》(A.Clowes and M.Reidy)中，我们将制作 使用动物模型来确定细胞凋亡增加的贡献 基质金属蛋白酶的表达与纤维帽萎缩有关。我们会 试图在大鼠身上证明刚性包裹导致的管腔狭窄 模拟晚期人类动脉粥样硬化性颈内动脉的状态 并导致细胞死亡和内膜基质退化，这是一个过程 这可能取决于某些次级应激信号通路。在……里面 Grant 3(S.M.Schwartz和D.Dichek)，我们将定义蛋白酶 在人类损伤中导致细胞死亡的级联反应及其相关性 手术标本中发现有帽状变薄的MR证据。我们 也将检验某些纤维帽不会破裂的假设 这是因为抗凋亡基因的表达增加。最后，我们 将尝试减少或增强载脂蛋白原中纤维帽的稳定性 通过选择促或抗凋亡基因的基因转移来获得E缺陷小鼠。 这些合作研究应该为基本的 纤维帽萎缩和断裂的机制。

The rupture of the fibrous cap is the critical event leading to thromboembolic complications on the luminal surface of advanced atherosclerotic plaques. The factors that set the stage for plaque disruption include progressive cap atrophy with loss of cells and matrix. Unfortunately, these beliefs are hard to test because of a lack of animal models. We propose to solve this problem by an interdisciplinary approach combining human tissue and animal model studies of molecular pathways that could underlie this process. In Grant 1 (T. Hatsukami and C. Yuan), we will study, using high resolution magnetic resonance imaging, a cohort of patients with moderate internal carotid artery stenosis. We will test the hypothesis that the fibrous caps of these lesions generally are thick and that thinning of the cap develops after the plaque enlarges and the lumen narrows. We will also determine whether ischemic neurological events or plaque rupture assessed by histological evaluation of excised plaques correlates with fibrous cap thinning. In Grant 2 (A. Clowes and M. Reidy), we will make use of animal models to define the contribution of increased apoptosis and matrix metalloproteinase expression to fibrous cap atrophy. We will attempt to demonstrate in rats that luminal narrowing by a rigid wrap models the state of an advanced human atherosclerotic internal carotid artery and causes cell death and intimal matrix degradation, a process that might depend upon certain secondary stress signaling pathways. In Grant 3 (S.M. Schwartz and D. Dichek), we will define the protease cascade leading to cell death in human lesions and correlate these findings in operative specimens with MR evidence of cap thinning. We will also test the hypothesis that certain fibrous caps do not rupture because of increased expression of anti-apoptotic genes. Finally, we will attempt to diminish or enhance the stability of fibrous caps in apo E deficient mice by gene transfer of select pro-or anti-apoptotic genes. These collaborative studies should provide novel insights into the basic mechanisms underlying fibrous cap atrophy and disruption.