Notch-Gridlock Signaling in Vascular Specification

血管规范中的Notch-Gridlock信号传导

• 批准号: 6838222
• 负责人: TAO P ZHONG
• 金额: $ 30.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-23 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838222
• 关键词: alternatives to animals in research; angiogenesis; biofeedback; biological signal transduction; cell cell interaction; cell differentiation; cell migration; confocal scanning microscopy; developmental genetics; gene expression; gene mutation; genetic promoter element; genetic regulation; genetically modified animals; green fluorescent proteins; high throughput technology; in situ hybridization; protein quantitation /detection; protein signal sequence; time resolved data; transcription factor; vascular endothelium; zebrafish

DESCRIPTION (provided by applicant): Vascular development requires a complex series of events during which endothelial cells differentiate from angioblast progenitors and assemble into the dorsal aorta and the cardinal vein, comprising the original circulatory loop. Arteries and veins are morphologically, functionally and molecularly different. How this distinction is established at cellular and molecular levels in the early stage of vasculogenesis is largely unknown. New genetic evidence from zebra fish studies suggests that the Notch signal transduction pathway is required for vascular specification. The gridlock gene, encoding an Enhancer of Split-related bHLH protein, mediates Notch signaling to promote development of the embryonic arteries. The research proposal explains how cellular and genetic analysis are used in zebra fish to understand the role of notch-gridlock pathway in regulating arterial/venous endothelial fate of angioblasts. Specially, this proposal first aims to identify potential cell-cell interactions by following angioblast migration. Next, experiments are designed to examine expression pattern of Notch signaling components in vascular development, as well as to determine the fate of individual angioblasts that are incapable of normal Notch signaling. The final experiments are proposed to test the mechanism by which gridlock mediates Notch signaling via a negative feedback loop. As fundamentals of vascular development are conserved between vertebrates and mammals, understanding the notch-gridlock signaling pathway in zebrafish will provide insights into mechanisms of vascular development as well as advance our understanding of etiologies of many human arterial diseases.

描述（由申请人提供）：血管发育需要一系列复杂的事件，在此期间，内皮细胞与血管生成祖细胞区分开，并组装到背主动脉和基本静脉中，包括原始的循环循环。动脉和静脉在形态，功能和分子上都是不同的。在血管生成早期，在细胞和分子水平上如何建立这种区别在很大程度上尚不清楚。 斑马鱼研究的新遗传证据表明，血管规范需要Notch信号转导途径。编码分裂相关BHLH蛋白的增强子的僵局基因介导了Notch信号传导以促进胚胎动脉的发展。该研究建议解释了如何在斑马鱼中使用细胞和遗传分析，以了解Notch-Gridlock途径在调节血管细胞的动脉/静脉内皮命运中的作用。 特别是，该提案首先旨在通过遵循血管细胞迁移来识别潜在的细胞 - 细胞相互作用。接下来，实验旨在检查血管发育中Notch信号成分的表达模式，并确定无法正常Notch信号传导的单个血管细胞的命运。提出了最终的实验，以测试僵局通过负反馈循环介导缺口信号传导的机制。 由于脊椎动物和哺乳动物之间的血管发育基本原理是保守的，因此了解斑马鱼中的Notch-Gridlock信号传导途径将提供有关血管发育机制的见解，并促进我们对许多人类动脉疾病的病因的理解。