Program Project: The Atherogenic Microenvironment

描述(由申请人提供)： 与动脉粥样硬化病变的开始和发展相关的细胞过程仍然不完全清楚。这一新的PPG的综合、统一的主题是定义致动脉粥样硬化的微环境如何异常地招募和改变造血细胞和血管细胞的功能，最终导致复杂的动脉粥样硬化斑块。通过研究血液传播细胞在动脉粥样硬化形成中的作用及其随后的细胞和化学修饰，所有五个项目负责人都将试图破译那些触发斑块形成的信号。这种PPG建立在动脉粥样硬化脂质和生长因子改变细胞募集和促进平滑肌细胞和巨噬细胞来源的泡沫细胞形成的假设基础上。项目1将定义清道夫受体(如CD36)在氧化低密度脂蛋白的吸收和代谢中的生理作用，重点介绍脂质积累影响病变细胞胆固醇吸收和外流的机制。我们还将确定这些受体在调节脂肪酸代谢和胰岛素抵抗方面对动脉粥样硬化病变发展的影响。项目2将评估胆固醇调节和脂蛋白相互作用对单核/巨噬细胞功能的影响，如迁移。在项目3中，我们将从机制上评估动脉粥样硬化环境中的脂质和细胞因子如何影响单核细胞的分化、运输和命运，有利于向泡沫细胞的分化和它们在病变中的滞留。由于康奈尔大学的研究小组已经证明，与神经系统和骨髓相关的生长因子也可以促进动脉粥样硬化病变的发展和组织重塑，因此，项目4专门设计来定义在招募到动脉中时，对血管生成生长因子(如血管生成生长因子)反应的细胞前体如何促进动脉粥样硬化形成。在项目5中，将确定生长因子的蛋白水解性切割在动脉粥样硬化发展中调节细胞募集和细胞凋亡的作用，以及与病变重塑相关的过程。每个项目具体建立在本计划中其他项目构思的许多概念的基础上。这些核心旨在协助PPG的行政职能，并提供和集中执行计划中的组织学和免疫组织化学实验所需的服务。此外，还将对许多项目中概述的动脉粥样硬化组织和共培养物进行电子显微镜/图像分析。预计我们的实验结果将促进我们对导致人类动脉粥样硬化性病变进展的细胞因素的知识基础。

DESCRIPTION (provided by applicant): Cellular processes related to the initiation and progression of the atherosclerotic lesion remain incompletely defined. The integrated, unifying theme of this new PPG is to define how the atherogenic micro- environment of the vessel wall aberrantly recruits and modifies the function of hematopoietic and vascular cells leading ultimately to the complex atheromatous plaque. By studying the role of blood borne cells in atherogenesis and their subsequent cellular and chemical modification, all five project leaders will attempt to decipher those signals that trigger plaque formation. This PPG is based on the hypothesis that atherogenic lipids and growth factors modify cellular recruitment and promote smooth muscle cell and macrophage-derived foam cell formation. Project 1 will define the physiological role of scavenger receptors (e.g. CD36) in the uptake and metabolism of oxidized LDL, focusing on the mechanisms by which lipid accumulation impacts cholesterol uptake and efflux in lesional cells. We will also determine the impact on these receptors in regulating fatty acid metabolism and insulin resistance on atherosclerotic lesion development. Project 2 will assess the effects of cholesterol modulation and lipoprotein interactions on monocyte/macrophage functions such as migration. In Project 3, we will assess mechanistically how lipids and cytokines of the atherogenic environment affect the differentiation, trafficking, and fate of monocytes favoring differentiation into foam cells and their retention in the lesion. Since the Cornell group has demonstrated that growth factors associated with the nervous system and bone marrow can also contribute to atherosclerotic lesion development and tissue remodeling, Project 4 is crafted specifically to define how cell progenitors responsive to angiogenic growth factors (e.g. VEGF) can promote atherogenesis when recruited into arteries. In Project 5, the role of proteolytic cleavage of growth factors modulating cell recruitment and apoptosis in the developing atheroma will be defined as well as processes related to lesion remodeling. Each project specifically builds on many of the concepts conceived by the other projects in this Program. The Cores are designed to assist in administrative functions of the PPG and to provide and centralize those services necessary to perform the planned histological and immunohistochemical experiments. In addition, electron microscopic/image analyses will be performed on the atherosclerotic tissue and co-cultures as outlined in many of the projects. It is anticipated that our experimental results will advance our knowledge base of the cellular factors that are responsible for the progression of the human atheromatous lesion.