Regulation of Endothelial Cell Function in Angiogenesis

血管生成是指从已有的血管系统中生成新的血管。这是一个复杂的过程，需要内皮细胞从底层基膜分离，启动增殖程序，向刺激点迁移，然后退出细胞周期，重新连接细胞外基质，并重新建立细胞间连接，形成功能性的三维管状阵列。该项目将重点关注内皮细胞参与“血管生成开关”的动态行为，以及导致内皮细胞参与“血管生成开关”的动态行为，并导致形成稳定的血液流动管道。我们计划四个紧密交叉的项目，每个项目都解决了血管生成内皮细胞表型的一个新方面。项目1将研究内皮细胞以丝氨酸蛋白酶（纤溶酶）的形式获得细胞表面蛋白水解的分子机制。新开发的膜联蛋白II缺失小鼠和膜联蛋白II启动子- lacz转基因小鼠将被用来确定几种血管生成中膜联蛋白II的需求，以及其由动脉粥样硬化血栓形成氨基酸，同型半胱氨酸调节，血栓反应蛋白-1与其细胞表面受体CD36相互作用并激活信号通路。最近开发的CD36缺失小鼠将作为一种独特的试剂来检测该系统在血管生成中的作用。项目3将致力于鉴定和表征一种独特的g蛋白偶联受体，该受体介导CXC类趋化因子的血管生成作用。本项目将研究该受体（一种假定的异二聚体）及其配体和细胞内信号蛋白的共刺激需求。项目4将考虑骨髓来源的内皮祖细胞的动员和募集，以及它们在伤口愈合和其他新生血管反应过程中参与血管生成。所有四个项目都将广泛利用三个支助设施。行政核心将为该计划提供预算、秘书和组织支持服务。Histotechnology Core将在组织采购、处理和成像方面提供技术专长和实际协助。动物模型核心将提供一系列体内模型系统，用于分析、处理和成像。动物模型中心将提供一系列体内模型系统，用于分析小鼠血管生成。总之，我们相信这个项目的核心体现了一个动态的、互动的和富有成效的项目，在强有力的制度支持下，将成功地阐明新的机制和范式，从而启发我们对血管生成过程的理解。

Angiogenesis is the proliferation of new blood vessels from pre-existing vasculature. It is a complex process which requires that the endothelial cell dissociate from underlying basement membrane, initiate a proliferative program, migrate toward a stimulus, and then exit the cell cycle, renew attachment to extracellular matrix, and re-establish inter- cellular junctions forming a functional three-dimensional tubular array. This program project will focus on the dynamic behaviors of the endothelial cell which characterize its participation in the "angiogenic switch" and which lead dynamic behaviors of the endothelial cell which characterize its participation in the "angiogenic switch" and which lead to formation of a stable conduit for flowing blood. We plan four closely interdigitating projects each of which addresses a novel aspect of the angiogenic endothelial cell phenotype. Project 1 will examine the molecular mechanism by which the endothelial cell acquires cell surface proteolytic in the form of the serine protease, plasmin. Newly developed annexin II null mice and annexin II promoter-LacZ transgenic mice will be employed to define the requirement for annexin II, as well as its regulation by the atherothrombotic amino acid, homocysteine, in several angiogenesis, thrombospondin-1, interacts with its cell surface receptor CD36 and activates a signaling pathway. Recently developed CD36 null mice will serve as a unique reagent for examining this system in angiogenesis. Project 3 will address the identification and characterization of a unique G-protein coupled receptor that mediates the angiogenesis effects of the CXC class of chemokines. This project will investigate the co-stimulatory requirements of the receptor, a putative heterodimer, as well as its ligands and intracellular signaling proteins. Project 4 will consider the mobilization and recruitment of bone marrow- derived endothelial progenitor cells and their participation in angiogenesis during the wound healing and other neovascular responses. All four projects will make extensive use of three support facilities. An Administrative Core will provide budgetary, secretarial, and organization support services to the program. A Histotechnology Core will supply technical expertise and practical assistance with tissue procurement, processing, and imaging. An Animal Models Core will provide a series of in vivo model systems for the analysis of processing, and imaging. An Animals Models Core will provide a series of in vivo model systems for the analysis of angiogenesis in mice. In summary, we believe that the projects and cores of this program embody a dynamic, interactive, and productive program that, with strong institutional support, will succeed in elucidating new mechanisms and paradigms to enlighten our understanding of angiogenic processes.