Program Project: The Atherogenic Microenvironment

计划项目：致动脉粥样硬化微环境

基本信息

批准号：
7228514
负责人：
DAVID P HAJJAR
金额：
$ 207.13万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-15 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7228514
关键词：
Program Project Atherogenic Microenvironment

项目摘要

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.

描述（由申请人提供）：与动脉粥样硬化病变的启动和进展有关的细胞过程仍未完全定义。这个新PPG的综合统一主题是定义血管壁的动脉粥样硬化微环境如何使造血细胞和血管细胞的功能最终导致复杂的动脉瘤斑块的功能。通过研究血液传播细胞在动脉粥样硬化及其随后的细胞和化学修饰中的作用，所有五个项目领导者都将试图破译那些触发斑块形成的信号。该PPG基于以下假设：动脉粥样硬化脂质和生长因子修饰细胞募集，促进平滑肌细胞和巨噬细胞衍生的泡沫细胞的形成。项目1将定义清道夫受体（例如CD36）在氧化LDL的摄取和代谢中的生理作用，重点是脂质积累影响胆固醇的胆固醇摄取和流行细胞的流出。我们还将确定对这些受体调节脂肪酸代谢和胰岛素耐药性对动脉粥样硬化病变发育的影响。项目2将评估胆固醇调节和脂蛋白相互作用对单核细胞/巨噬细胞函数（例如迁移）的影响。在项目3中，我们将从机械上评估动脉粥样硬化环境的脂质和细胞因子如何影响单核细胞的分化，运输和命运，从而有利于分化为泡沫细胞及其在病变中的保留率。由于康奈尔（Cornell）组已证明与神经系统和骨髓相关的生长因子也可以有助于动脉粥样硬化病变的发育和组织重塑，因此专门制作了项目4，以定义细胞祖细胞对血管生成因子（例如VEGF）的反应效应时，可以在招募植物时促进动脉生成。在项目5中，将定义调节细胞募集和凋亡的生长因子蛋白水解裂解的作用，并定义与病变重塑有关的过程。每个项目都专门建立在该计划中其他项目所构想的许多概念上。核心旨在协助PPG的行政职能，并提供和集中那些执行计划的组织学和免疫组织化学实验所需的服务。此外，将在许多项目中概述的动脉粥样硬化组织和共培养上进行电子微观/图像分析。预计我们的实验结果将提高我们对人动脉瘤病变进展的细胞因子的知识基础。