Role of fibronectin in vascular plexus self-organization during embryogenesis

描述（由申请人提供）：中胚层祖细胞的血管形成（血管发生）是胚胎发育和某些病理生理学共同的基本过程。最近，我们发现成血管细胞的血管索的形成涉及广泛的侵入活动。在这个过程中，血管生成萌芽，一组内皮细胞侵入数百微米的无血管区域，从而奠定了原始血管丛的结构。我们的目的是确定纤连蛋白的具体作用，其主要的内皮细胞受体的过程中。具体地说，我们将（1）确定纤连蛋白是否在血管生成出芽过程中作为指导线索，（2）研究细胞介导的短暂的、富含纤连蛋白的细胞外基质在原始内皮细胞索周围的宏观组装动力学和周转，（3）确定细胞粘附复合物的分子组成以及整合素avb 3和a5 b 1的各自作用，（4）将实验数据综合成血管发生的定量模型。血管生成发芽将在体内进行研究，通过自动光学显微镜和荧光标记的抗体和GFP构建体的组合，在存在或不存在干扰试剂。该项目的长期目标是充分详细地了解内皮细胞-ECM相互作用，以构建预测性定量模型，用于组织工程或了解发育形态发生过程。 了解血管发育具有压倒性的临床重要性。我们的目标和其他血管生物学家的目标是解释促进或抑制血管生长的机制，从而调节血管网络的结构。特别地，内皮祖细胞是治疗性血管化策略、组织工程和阻断肿瘤生长的尝试的焦点。

DESCRIPTION (provided by applicant): Vessel formation from mesodermal progenitors, vasculogenesis, is a fundamental process common to both embryonic development and certain pathophysiologies. Recently we showed that the formation of vascular cords from isolated clusters of angioblasts involves extensive invasive activity. During this process, vasculogenic sprouting, a group of endothelial cells invades hundreds of micrometers into avascular areas, and thereby lays down the structure of the primordial vascular plexus. We aim to determine the specific role of fibronectin, and its major endothelial receptors in the process. Specifically, we will (1) determine if fibronectin acts as a guidance cue during vasculogenic sprouting, (2) study the cell-mediated macro- assembly dynamics and turnover of the transient, fibronectin-rich extracellular matrix surrounding the cords of primordial endothelial cells, (3) determine the molecular composition of cell adhesion complexes and the respective roles of integrins avb3 and a5b1, and (4) synthesize the experimental data into a quantitative model of vasculogenesis. Vasculogenic sprouting will be studied in vivo, through automated optical microscopy and a combination of fluorescence-tagged antibodies and GFP constructs, in the presence or absence of perturbing reagents. The long term goal of the project is to understand endothelial cell-ECM interactions in sufficient detail to allow the construction of predictive quantitative models, either for tissue engineering, or to understand developmental morphogenetic processes. Understanding blood vessel development is of overwhelming clinical importance. Our goal, and the goal of other vascular biologists, is to explain the mechanisms that promote or inhibit vessel growth and thus regulate the structure of the vessel network. In particular, endothelial progenitors are in the focus of therapeutic vascularization strategies, tissue engineering, and attempts to block tumor growth.