Integrating Cell Division and Morphogenesis in Developing Vessels

描述（由申请人提供）：为了制造合适的血管，必须调节和整合几个主要的细胞过程。具体而言，内皮细胞分裂发生在形态发生过程的背景下，导致芽形成，融合和血管网络的扩张。通常，这些不同的过程优雅地交织在一起，以产生具有适当三维模式的适当数量的脉管系统。然而，人们对血管生成过程中内皮细胞分裂和形态发生在空间和时间上是如何调节的知之甚少，对这些过程如何整合形成血管的了解更少。我们有证据表明，内皮细胞分裂的两个主要方面是由形态发生的线索，细胞分裂的速度和有丝分裂过程中的分裂面的方向。因此，我们假设形态发生信号影响内皮细胞分裂的特定参数，并且这种输入对于正确的血管形态发生至关重要。我们还假设，形态发生信号影响的速度和方向的内皮细胞分裂是通过内皮细胞连接和有丝分裂极性组件转导。为了验证这些假设，我们将使用动态成像来阐明血管生成过程中内皮细胞分裂在时间和空间上受到调节的“规则”。我们将操纵影响纺锤体动力学的内皮连接和极性分子，并确定这些操纵对细胞分裂和极性的影响。最后，我们将详细研究两种信号传导途径，VEGF和平面细胞极性（PCP或非经典Wnt信号传导）在内皮形态发生和细胞分裂之间的协调中的作用。对血管生成过程中细胞过程如何整合的分子理解将有助于设计血管再生的方法。重现导致适当血管形成的生物过程的能力是再生医学许多方面的要求，因此这项工作将在这一转化竞技场中产生很大影响。该提案将使用小鼠模型来研究构成血管壁的细胞的繁殖如何影响血管的形式和形状。研究结果将帮助我们了解血管是如何成形的，这反过来将有助于设计制造用于治疗的人造血管的方法。

DESCRIPTION (provided by applicant): To make a proper blood vessel, several major cellular processes must be regulated and integrated. Specifically, endothelial cell division occurs in the context of morphogenetic processes that lead to sprout formation, fusion, and expansion of the vascular network. Normally these distinct processes are elegantly interwoven to produce the appropriate amount of vasculature with the proper 3-dimensional pattern. However, relatively little is known about how endothelial cell division and morphogenesis are regulated in space and time during angiogenesis, and even less is known about how these processes integrate to form blood vessels. We have evidence that two major aspects of endothelial cell division are regulated by morphogenetic cues, the rate of cell division and the orientation of the cleavage plane during mitosis. Thus we hypothesize that morphogenetic signals impact specific parameters of endothelial cell division, and that this input is critical to proper vessel morphogenesis. We also hypothesize that morphogenetic signals affecting the rate and orientation of endothelial cell division are transduced via endothelial cell-cell junctions and mitotic polarity components. To test these hypotheses, we will use dynamic imaging to elucidate the "rules" by which endothelial cell division is regulated in time and space during angiogenesis. We will manipulate endothelial junctions and polarity molecules that affect spindle dynamics, and determine the impact of these manipulations on cell division and polarity. Finally, we will examine in detail the role of two signaling pathways, VEGF and Planar Cell Polarity (PCP or non-canonical Wnt signaling) in the co- ordination between endothelial morphogenesis and cell division. A molecular understanding of how cellular processes are integrated during angiogenesis will help in the design of approaches to vessel regeneration. The ability to recapitulate biological processes leading to proper vessel formation is a requirement for many aspects of regenerative medicine, so this work will have high impact in this translational arena. This proposal will use mouse models to examine how the propagation of cells making up the wall of blood vessels affects the form and shape of the vessel. The results will help us understand how vessels are shaped, which in turn will aid in designing ways to make artificial vessels for therapeutic use.