Elucidating the transcriptional mechanisms regulating shear stress mediated gene expression and their role during blood vessel pruning

血管系统由分叉的内皮小管网络组成。为了建立这个血管网络，内皮细胞必须协调各种不同的细胞过程。内皮细胞需要根据趋化信号进行迁移、增殖和随后的分化。最近的遗传学研究发现了一些与血管萌发有关的关键因素。这些受体包括血管内皮生长因子、Notch和G蛋白偶联受体。然而，对于给定内皮细胞内这些通路的空间和时间激活以及这些不同通路的输入是如何整合的，人们知之甚少。特别是，我们不理解相邻的血管如何在彼此接近的情况下导航，而不对相同的引导信号做出反应。这项拟议的研究旨在利用斑马鱼模型系统中活体成像和遗传操作的最新进展，解决血管生成中的三个基本问题。我们将描述内皮细胞分裂在血管构型过程中的作用，并研究不对称分布的细胞命运决定因素在这一过程中的参与。然后，我们将解决在血管生成萌发过程中如何建立区域差异以及趋化因子信号如何在这一过程中发挥作用的问题。最后，我们将进行一次筛选，以识别对正常血管萌发至关重要的新球员。

The vasculature consists of a ramified network of endothelial tubules. In order to establish this vascular network, endothelial cells must coordinate a variety of different cellular processes. Endothelial cells need to migrate in response to chemotactic cues, proliferate and subsequently differentiate. Recent genetic studies have uncovered a number of key players that are involved in blood vessel sprouting. These include VEGF, Notch and G-protein coupled receptors. However, little is known about the spatial and temporal activation of these pathways within a given endothelial cell and how the inputs from these divergent pathways are integrated. In particular, we do not understand how neighbouring blood vessels navigate in close proximity to one another without responding to the same guidance cues. The proposed research aims to address three fundamental questions in angiogenesis, making use of recent progress in in vivo imaging and genetic manipulations in the zebrafish model system. We will delineate the contribution of endothelial cell divisions during vascular patterning and study the involvement of asymmetrically distributed cell fate determinants in this process. We will then address the question how regional differences are established during angiogenic sprouting and how chemokine signalling contributes to this process. Finally, we will carry out a screen aiming at the identification of new players important for proper blood vessel sprouting to occur.