MECHANISMS OF FIBROUS CAP ATROPHY

描述 （改编自申请人的摘要）纤维帽的破裂是 导致管腔血栓栓塞并发症的严重事件 晚期动脉粥样硬化斑块的表面。 奠定基础的因素 斑块破裂的原因包括进行性冠状萎缩伴细胞丢失， 矩阵 不幸的是，这些信念很难测试，因为缺乏 动物模型 调查小组建议通过以下方式解决这一问题： 结合人体组织和动物模型研究的跨学科方法 可能是这个过程的基础。 在Grant 1（T. Hatsukami和C. Yuan），他们将使用高分辨率磁 共振成像，中度颈内动脉狭窄患者队列 动脉狭窄 他们将测试的假设，即纤维帽 这些损伤通常是厚的， 在斑块扩大和管腔变窄之后。 他们还将确定 是否评估缺血性神经系统事件或斑块破裂， 与纤维帽相关的切除斑块的组织学评价 变薄 在Grant 2（A. Clowes和M. Reidy），他们将利用 动物模型，以确定增加的细胞凋亡和基质 金属蛋白酶表达与纤维帽萎缩的关系。 他们将试图 在大鼠中证明，通过刚性包裹使管腔变窄， 一个先进的人类动脉粥样硬化颈内动脉，并导致细胞 死亡和内膜基质降解，这一过程可能取决于 某些次级压力信号通路 在格兰特3（S.M.施瓦茨和 D. Dichek），他们将定义导致细胞死亡的蛋白酶级联反应， 并将手术标本中的这些发现与MR相关联 盖变薄的证据。 他们还将测试假设， 纤维帽不破裂，因为表达增加， 抗凋亡基因。 最后，他们将试图减少或加强 基因转移筛选载脂蛋白E基因缺陷小鼠纤维帽稳定性 促或抗凋亡基因。 这些合作研究应提供 对纤维帽萎缩的基本机制的新见解， 破坏

DESCRIPTION (Adapted from Applicant's Abstract) 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 of 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. The investigative team proposes 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), they will study, using high resolution magnetic resonance imaging, a cohort of patients with moderate internal carotid artery stenosis. They 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. They 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), they will make use of animal models to define the contribution of increased apoptosis and matrix metalloproteinase expression to fibrous cap atrophy. They 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), they 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. They will also test the hypothesis that certain fibrous caps do not rupture because of increased expression of anti-apoptotic genes. Finally, they 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.