CELL SURVIVAL PATHWAYS

纤维帽的破裂是导致 血栓栓塞并发症的管腔表面先进的 动脉粥样硬化斑块 为牙菌斑奠定基础的因素 破坏包括进行性帽萎缩伴细胞损失， 矩阵不幸的是，这些信念很难测试，因为缺乏 动物模型。 我们建议通过一个 结合人体组织和动物模型的跨学科方法 对可能构成这一过程的分子途径的研究。 在 格兰特1（T. Hatsukami和C.元），我们将研究，使用高分辨率 磁共振成像，一个队列的患者中度内部 颈动脉狭窄 我们将检验纤维组织 这些病变的冠通常较厚， 在斑块扩大和管腔变窄之后发展。 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价进行评估， 纤维帽变薄。 在Grant 2（A. Clowes和M. Reidy），我们将 使用动物模型确定细胞凋亡增加的作用 基质金属蛋白酶表达与纤维帽萎缩的关系。 我们将 试图在大鼠中证明， 模拟了晚期人类动脉粥样硬化颈内动脉的状态 动脉，并导致细胞死亡和内膜基质降解，一个过程 这可能取决于某些次级压力信号通路。 在 格兰特3（S.M. Schwartz和D. Dichek），我们将定义蛋白酶 级联导致人类病变中的细胞死亡，并将这些 在手术标本中发现的MR证据帽变薄。 我们 还将检验某些纤维帽不会破裂的假设 因为抗凋亡基因的表达增加。 最后我们 将试图减少或增强APO中纤维帽的稳定性 通过基因转移选择促或抗凋亡基因的E缺陷小鼠。 这些合作研究应该提供新的见解的基本 纤维帽萎缩和破坏的潜在机制。

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.