Molecular Regulation of Vascular Sprout Formation

项目摘要/摘要 萌芽血管生成，即血管萌芽的形成，对于建立复杂的和 维持生命所需的高度分枝的维管束树。这一过程在伤口愈合中也起着关键作用。 和器官再生。此外，过多、过少或以其他方式异常的萌芽形成也是相关的 患有多种疾病。因此，萌芽血管生成的治疗操作引起了人们的极大兴趣。 然而，要做到这一点，我们必须首先剖析调控这一重要过程的分子机制。这 正是这一开创性提案的首要目标，第一个解决血管内皮细胞如何 生长因子(VEGF)和Semaphorin-PlexinD_1(Sema-PlxnD_1)途径通过三个共享的途径相互作用 分子组成和决定萌芽形成的基本方面，如丰度， 血管分支的位置和形状。这里描述的实验利用了互补的 斑马鱼和培养的内皮细胞作为萌发血管生成模型系统的优势， 利用创新的转录后基因表达荧光记者和斑马鱼新突变体 三个共享路径组件中的每一个。通过阐明血管内皮生长因子和Sema-PlxnD1是如何相互作用的 目前的研究将为内皮细胞用于整合的分子机制提供关键的见解 芽形成过程中的相反输入，并为治疗操作提供了新的分子靶点 这一过程。这样的新疗法可以帮助保护有失明风险的人的视力，因为 过度的角膜血管形成(渗出性黄斑变性)，恢复正常的血液供应 在许多癌症患者中，通过使肿瘤正常化来抑制肿瘤的生长和扩散 肿瘤血管系统。

PROJECT SUMMARY/ABSTRACT Sprouting angiogenesis, the formation of blood vessel sprouts, is essential for building the complex and highly branched vascular tree required to sustain life. This process also plays pivotal roles in wound healing and organ regeneration. In addition, too much, too little or otherwise abnormal sprout formation is associated with many diseases. Thus, there is much interest in the therapeutic manipulation of sprouting angiogenesis. However, to achieve this we must first dissect the molecular mechanisms that regulate this vital process. This is precisely the overarching goal of this pioneering proposal, the first to address how the Vascular Endothelial Growth Factor (VEGF) and Semaphorin-PlexinD1 (Sema-PlxnD1) pathways interact via three shared molecular components and determine fundamental aspects of sprout formation, such as the abundance, positioning and shape of vascular branches. The experiments described here exploit the complementary advantages of the zebrafish and cultured endothelial cells as model systems for sprouting angiogenesis, employ innovative fluorescent reporters of post-transcriptional gene expression and novel zebrafish mutants of each of the three shared pathway components. By elucidating how VEGF and Sema-PlxnD1 interact the present study will provide key insights into the molecular mechanisms that endothelial cells use to integrate opposing inputs during sprout formation and suggest novel molecular targets for therapeutic manipulation of this process. Such new therapies could help to preserve the sight of people at risk for blindness due to excessive corneal vascularization (exudative macular degeneration), restore proper blood supply to those suffering from ischemia and limit the growth and spread of tumors in many cancer patients by normalizing their tumor vasculature.