Integrating Cell Division and Morphogenesis in Developing Vessels

将细胞分裂和形态发生整合到发育中的血管中

• 批准号: 7655236
• 负责人: Victoria L Bautch
• 金额: $ 36.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655236
• 关键词: 3-Dimensional; Affect; Biological; Biological Assay; Biological Process; Blood Vessels; Cell Polarity; Cell division; Cell physiology; Cells; Cues; Endothelial Cells; Event; Goals; Image; In Situ; Intercellular Junctions; Lead; Microtubules; Mitosis; Mitotic; Modeling; Molecular; Morphogenesis; Natural regeneration; Outcome; Pathway interactions; Pattern; Positioning Attribute; Process; Reagent; Regenerative Medicine; Reporter Genes; Retina; Rodent; Role; Shapes; Signal Pathway; Signal Transduction; Staging; Techniques; Testing; Therapeutic Uses; Time; Tubulin; Vascular Endothelial Growth Factors; Work; angiogenesis; design; embryonic stem cell; mouse model; novel; time orientation

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.

描述（由申请人提供）：为了制作适当的血管，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，导致血管网络的发芽形成，融合和膨胀。通常，这些不同的过程优雅地交织在一起，以适当的3维模式产生适当数量的脉管系统。然而，关于在血管生成期间如何调节内皮细胞分裂和形态发生的情况相对较少，对于这些过程如何整合形成血管的时间和时间更少。我们有证据表明，内皮细胞分裂的两个主要方面受形态发生线索的调节，细胞分裂的速率和有丝分裂期间裂解平面的方向。因此，我们假设形态发生信号会影响内皮细胞分裂的特定参数，并且该输入对于适当的血管形态发生至关重要。我们还假设，影响内皮细胞分裂速率和方向的形态发生信号通过内皮细胞 - 细胞连接和有丝分裂极性成分转导。为了检验这些假设，我们将使用动态成像来阐明在血管生成期间在时间和空间中调节内皮细胞分裂的“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通路，VEGF和平面细胞极性（PCP或非规范WNT信号传导）在内皮形态发生和细胞分裂之间的共同点中的作用。对血管生成过程中细胞过程的整合方式的分子理解将有助于设计血管再生方法。概括导致适当血管形成的生物学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个翻译领域产生很大的影响。该建议将使用小鼠模型来检查构成血管壁的细胞的传播如何影响血管的形式和形状。结果将有助于我们了解船只的形状，这反过来将有助于设计制造人造血管以供治疗的方法。