CRITICAL TRANSITIONS IN ATHEROGENESIS

动脉粥样硬化及其毁灭性的临床并发症-动脉 血栓形成、缺血和心脏、大脑和其他 重要器官、破裂的主动脉瘤和外周血管 不足-继续占发病率的大部分 以及工业化国家成年人口的死亡率。 尽管我们对脂质代谢的理解有了重大进展 及其在促进动脉粥样硬化形成中的作用， 了解动脉粥样硬化的病理学，特别是， 高胆固醇血症等全身性风险因素如何影响 进行性狭窄/重塑、瘢痕形成/钙化，以及 在动脉粥样硬化斑块部位发现脂质积聚 阵 这个新的SCOR计划的主要重点将是 动脉粥样硬化形成，发生在动脉粥样硬化中的事件的发病顺序， 导致临床疾病的动脉壁。 我们的目标是定义 参与某些关键的细胞和分子机制， 动脉粥样硬化斑块自然史的转变， 在其解剖定位和时间进展的基础上 易发生血管内血栓形成的不稳定/脆弱阶段。 项目目标包括：（1）发现内皮细胞诱导基因 通过血流动力学力导致局部损伤; (2)在体内测试基质降解蛋白酶的作用，和 促炎性和抗炎性细胞因子，对动脉 与斑块稳定性相关的结构;（3）探讨其作用机制 T淋巴细胞的募集及其在病变中的功能 进展/回归;（4）定义NF-κ B的作用- kappaB/IkappaB转录因子系统在调节 血管壁中动脉粥样硬化相关基因的表达;（5） 应用新兴的核磁共振技术 成像和血管内超声，在动物模型和人类 受试者，研究降脂的机制， 干预（饮食、药物）影响牙菌斑结构， 稳定 一个由基础研究人员组成的跨学科团队， 具有血管生物学专业知识的临床科学家， 心血管病理学和医学，以及生物力学 工程，已经组装在一个支持性的机构， 环境 这些研究应该产生新的见解 发病机制和有效的治疗干预， 动脉粥样硬化性心血管疾病

Atherosclerosis and its devastating clinical complications---arterial thrombosis, ischemia and infarction of the heart, brain and other vital organs, ruptured aortic aneurysms and peripheral vascular insufficiency---continue to account for the majority of the morbidity and mortality in the adult populations of industrialized nations. Despite major advances in our understanding of lipid metabolism and its role in promoting atheroma formation, much still remains to be learned about the pathobiology of atherosclerosis, in particular, how systemic risk factors such as hypercholesterolemia contribute to the progressive narrowing/remodeling, scarring/calcification, and lipid accumulation found at sites of atherosclerotic plaque formation. The primary focus of this new SCOR program will be atherogenesis, the pathogenetic sequence of events occurring within the arterial wall that leads to clinical disease. Our goal is to define the cellular and molecular mechanisms involved in certain critical transitions in the natural history of the atherosclerotic plaque, which underly its anatomical localization and temporal progression to an unstable/vulnerable stage predisposing to intravascular thrombosis. Project Aims include: (1) the discovery of endothelial genes induced by hemodynamic forces that contribute to localized lesion initiation; (2) testing in vivo the roles of matrix degrading proteinases, and pro-and anati-inflammatory cytokines, on aspects of arterial structure related to plaque stability; (3) exploring the mechanisms of recruitment of T-lymphocytes and their function(s) in lesion progression/regression; (4) defining the role of the NF- kappaB/IkappaB transcription factor system in the regulation of expression of atherosclerosis-related genes in the vascular wall; (5) applying the emerging technologies of nuclear magnetic resonance imaging and intravascular ultrasound, in animal models and human subjects, to study the mechanisms by which lipid-lowering interventions (dietary, pharmacologic) effect plaque structure and stability. An interdisciplinary team of basic investigators and clinician-scientists, with expertise in vascular biology, cardiovascular pathology and medicine, and biomechanical engineering, has been assembled in a supportive institutional environment. These studies should yield new insights into the pathogenesis and effective therapeutic interventions for atherosclerotic cardiovascular disease.