MECHANISMS OF FIBROUS CAP ATROPHY

描述 (改编自申请人的摘要)纤维帽的断裂是 导致管腔血栓栓塞症并发症的危重事件 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。调查组建议通过一种 结合人体组织和动物模型研究的跨学科方法 可能构成这一过程的分子途径。在授权书1中(T. Hatsukami和C.袁)，他们将使用高分辨率磁力进行研究 磁共振成像：一组中度颈内动脉疾病患者 动脉狭窄。他们将检验这样一种假设，即 这些病变通常较厚，导致帽状突起变薄。 在斑块扩大和管腔缩小之后。他们还将确定 无论是缺血性神经事件还是斑块破裂 切除斑块的组织学评价与纤维帽的相关性 变薄了。在《格兰特2》(A.Clowes和M.Reidy)中，他们将利用 用动物模型确定细胞凋亡和基质增加的作用 金属蛋白酶表达与纤维帽萎缩的关系。他们将尝试 在大鼠身上演示硬性包裹造成的管腔狭窄 一种晚期人类动脉粥样硬化性颈内动脉和引起细胞 死亡和内膜基质退化，这一过程可能取决于 某些次级应激信号通路。在Grant 3(S.M.Schwartz和 D.Dichek)，他们将定义导致细胞死亡的蛋白酶级联 并将手术标本中的这些发现与磁共振相关联 盖子变薄的证据。他们还将检验这一假设，即某些 纤维帽不会破裂，因为增加了 抗凋亡基因。最后，他们将试图减少或加强 SELECT基因转移对载脂蛋白E缺陷小鼠纤维帽稳定性的影响 支持或反对细胞凋亡的基因。这些合作研究应该提供 对纤维帽萎缩和纤维帽萎缩的基本机制的新见解 颠覆。

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.