Molecular Regulation of Vascular Sprout Formation

血管芽形成的分子调控

• 批准号: 9330927
• 负责人: Jesús Torres-Vázquez
• 金额: $ 60.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330927
• 关键词: Address; Alleles; Alternative Splicing; Attenuated; Binding; Biochemical; Biological Assay; Biological Models; Blindness; Blood Vessels; Cancer Patient; Cardiovascular system; Cell Culture Techniques; Complex; Cornea; Defect; Development; Disease; Dissection; Embryo; Endocytosis; Endothelial Cells; Equilibrium; Event; Exudative age-related macular degeneration; Family; Fishes; Gene Expression; Genetic; Genetic Transcription; Goals; Growth; Guanosine; In Vitro; Ischemia; KDR gene; Knowledge; Life; Link; Macular degeneration; Malignant Neoplasms; Molecular; Monomeric GTP-Binding Proteins; Mus; Nonmuscle Myosin Type IIA; Pathologic; Pathway interactions; Play; Positioning Attribute; Process; Protein Isoforms; Proteins; RGS19 gene; RNA Splicing; Recovery; Regulation; Reporter; Reporting; Research; Resolution; Risk; Role; Semaphorins; Shapes; Signal Pathway; Signal Transduction; Substrate Specificity; Testing; Therapeutic; Transgenic Organisms; Trees; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular blood supply; Vascularization; Vision; Wound Healing; Zebrafish; angiogenesis; base; blood vessel development; experimental study; in vivo; innovation; insight; interest; mRNA Stability; molecular targeted therapies; mutant; new therapeutic target; novel; novel therapeutics; organ regeneration; programs; public health relevance; receptor; tumor; vasculogenesis

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.

项目概要/摘要 发芽血管生成，即血管芽的形成，对于构建复杂和稳定的血管至关重要。 维持生命所需的高度分支的血管树。这个过程在伤口愈合中也起着关键作用 和器官再生。此外，发芽过多、过少或异常也与发芽有关。 与许多疾病。因此，人们对萌芽血管生成的治疗操作很感兴趣。 然而，为了实现这一目标，我们必须首先剖析调节这一重要过程的分子机制。这 正是这一开创性提案的总体目标，第一个解决血管内皮细胞如何 生长因子 (VEGF) 和 Semaphorin-PlexinD1 (Sema-PlxnD1) 通路通过三个共享通路相互作用 分子成分并决定芽形成的基本方面，例如丰度， 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血管生成模型系统的优势， 采用转录后基因表达的创新荧光报告基因和新型斑马鱼突变体 三个共享途径组件中的每一个。通过阐明 VEGF 和 Sema-PlxnD1 如何相互作用 本研究将为内皮细胞整合的分子机制提供重要见解 在芽形成过程中相反的输入，并提出了治疗操作的新分子靶点 这个过程。这种新疗法可能有助于保护因以下原因而面临失明风险的人的视力： 过度的角膜血管化（渗出性黄斑变性），恢复正常的血液供应 患有缺血并通过使肿瘤正常化来限制许多癌症患者的肿瘤生长和扩散 肿瘤血管系统。