ARTERIAL WALL AND ATHEROSCLEROSIS

动脉粥样硬化的发生以中膜平滑肌细胞的迁移为标志， 肌细胞进入内膜，在内膜中这些细胞增殖并产生 丰富的细胞外胶原纤维和弹性蛋白。 所得 基质的积累，加上其结合细胞外的能力， 脂质是动脉粥样硬化斑块质量增加的主要来源。 损伤。 本项目的总体目标是确定 和调节动脉基质的积累和降解， 特别是考虑到动脉粥样硬化因素的影响， 环境和细胞起源，从而有助于知识的基本 最终控制这一人类重大疾病的关键 为了达到这些目的， 我们将使用主动脉平滑肌细胞培养物， 作为正常和病变动脉的模型 墙 这些培养系统来自新生大鼠和兔主动脉， 分别表现出结构特征，基质和代谢 模拟动脉壁的反应。 因此，机会 是为了控制扰动或伤害暴露的程度， 表征相对自由的细胞内和细胞外调节反应 动脉组织分析的复杂性。 工作人员在 项目包括高级和初级教师和支持人员 成员，组成一个具有相当专业知识的调查小组 在生物化学的理论和实验方面， 细胞生物学和细胞外基质酶学。 领域 各个项目负责人的专业知识可以很好地互补， 他们的研究工作将高度整合， 分析细胞培养物的生物合成和降解反应 动脉粥样硬化损伤和扰动的模型。 项目27关注的是细胞培养模型的发展， 蛋白水解和脂质诱导的动脉损伤， 这些模型中胶原蛋白、弹性蛋白和脂蛋白的调节水平。 项目34将研究特定遗传类型的调节， 胶原评估转录控制机制，包括 调节元件和因子介导的表达，因为这些是 受致动脉粥样硬化刺激的影响。 第28章将关注 赖氨酰氧化酶在这些培养物中的调节和生物合成过程 系统. 赖氨酰氧化酶催化引发弹性蛋白交联 和胶原蛋白转化为不溶性纤维，从而可以控制 纤维化病变 项目36的重点是机制， 生长因子-I差异调节平滑肌细胞弹性生成 作为年龄、激素浓度和细胞类型的函数。 这些 项目由两个提供细胞培养的核心单位支持， 分子和免疫学探针、显微镜和行政支持 对这个项目至关重要。

The onset of atherosclerosis is marked by the migration of medial smooth muscle cells into the intima where these cells proliferate and produce abundant, extracellular fibers of collagen and elastin. The resulting accumulation of matrix, coupled with its ability to bind extracellular lipid, is a major source of the increasing mass of the atherosclerotic lesion. The overall goal of this project is to determine the mechanisms and regulation of arterial matrix accumulation and degradation with particular regard to the influence of atherogenic factors of both environmental and cellular origin, thus contributing knowledge essential to the eventual control of this major human disease. Toward these ends, we will employ aortic smooth muscle cell cultures which have been developed by our program as models of the normal and diseased arterial wall. These culture systems, derived from neonatal rat and rabbit aorta, respectively, exhibit structural features, matrices and metabolic responses which emulate those of the arterial wall. Thus, the opportunity is provided to control the extent of perturbant or injury exposure and to characterize intra- and extracellular regulatory responses relatively free of the analytical complexities of arterial tissue. The staff of this project includes both senior and junior faculty and supporting staff members, constituting a team of investigators with considerable expertise in the theoretical and experimental aspects of the biochemistry, molecular and cell biology, and enzymology of the extracellular matrix. The areas of expertise of the individual project leaders complement each other well, and their research efforts will be highly integrated to provide in depth analyses of the biosynthetic and degradative responses of the cell culture models to atherogenic injuries and perturbations. Project 27 is concerned with the development of cell culture models of proteolytic and lipid-induced arterial injury and with the definition of levels of regulation of collagen, elastin and lipoprotein in these models. Project 34 will investigate the regulation of specific genetic types of collagen assessing for transcriptional control mechanisms including regulatory elements and factors mediating expression, as these are influenced by atherogenic stimuli. Project 28 will be concerned with the regulation and biosynthetic processing of lysyl oxidase in these culture systems. Lysyl oxidase catalytically initiates crosslinking of elastin and collagen into insoluble fibers and thus can control the development of fibrotic lesions. Project 36 focuses on mechanisms whereby insulin-like growth factor-I differentially regulates smooth muscle cell elastogenesis as a function of age, hormone concentration, and cell type. These projects are supported by two core units providing cell cultures, molecular and immunological probes, microscopy and administrative support essential to this project.