Bidirectional Notch Signaling and Angiogenesis

双向Notch信号传导和血管生成

• 批准号: 7545483
• 负责人: CHRISTOPHER C. W. HUGHES
• 金额: $ 36.05万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-19 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545483
• 关键词: Acute; Address; Binding; Biological Assay; Blood; Blood Vessels; Blood capillaries; Cell Line; Cell Nucleus; Cell surface; Cells; Chromatin Structure; Collagen; Data; Development; Dominant-Negative Mutation; Down-Regulation; Elements; Embryo; Endothelial Cells; Event; Fibrin; Figs - dietary; Gel; Gene Expression; Gene Targeting; Genes; Implant; In Vitro; Inflammation; Inflammation Mediators; Integrins; Knowledge; Ligands; MMP2 gene; Malignant Neoplasms; Maps; Matrix Metalloproteinases; Mining; Modeling; Mus; Operative Surgical Procedures; Phenotype; Plug-in; Process; Proteins; Research Personnel; Resolution; Role; Signal Transduction; TNF gene; Tertiary Protein Structure; Testing; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Work; adapter protein; angiogenesis; capillary; falls; fight against; in vivo; jagged1 protein; matrigel; new growth; notch protein; programs; promoter; Acute; Address; Binding; Biological Assay; Blood; Blood Vessels; Blood capillaries; Cell Line; Cell Nucleus; Cell surface; Cells; Chromatin Structure; Collagen; Data; Development; Dominant-Negative Mutation; Down-Regulation; Elements; Embryo; Endothelial Cells; Event; Fibrin; Figs - dietary; Gel; Gene Expression; Gene Targeting; Genes; Implant; In Vitro; Inflammation; Inflammation Mediators; Integrins; Knowledge; Ligands; MMP2 gene; Malignant Neoplasms; Maps; Matrix Metalloproteinases; Mining; Modeling; Mus; Operative Surgical Procedures; Phenotype; Plug-in; Process; Proteins; Research Personnel; Resolution; Role; Signal Transduction; TNF gene; Tertiary Protein Structure; Testing; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Work; adapter protein; angiogenesis; capillary; falls; fight against; in vivo; jagged1 protein; matrigel; new growth; notch protein; programs; promoter

Notchl and its ligands are critical for blood vessel development and angiogenesis, as evidenced by the embryonic lethality observed when these genes are deleted in mice. While notch signaling is well charac- erized, "reverse signaling", through the ligands delta and jagged, has only recently been recognized,and its role in the vasculature is completely unknown. We have found that the inflammatory mediator TNF induces agged-1 expression in endothelial cells (EC), and in addition, induces genes associated with an angiogenic ip cell phenotype. Furthermore, jagged is involved in bi-directional signaling that helps to establish tip and trunk cell phenotypes in developing sprouts. Jagged signals through notch to induce the bHLHtranscription factor HESR1, and the subsequent down regulation of its target gene VEGFR2. Jagged also signals cell autonomously to the nucleus where it induces genes associated with a tip cell phenotype, such as VEGFR2 and PDGF-B, and promotes sprouting. In addition, TNF-induces 0^3 expression, which reinforces these divergent phenotypes by synergizing with notch signaling in trunk cells. TNF initially blocks sprouting, both in vitro and in vivo, but once removed, sprouting is augmented suggesting that TNF "primes" EC. Our preliminary data have led us, therefore, to the hypothesis that TNF and jagged cooperate to temporally coordinate the onset of angiogenesis with the resolution of acute inflammation. We will test this hypothesis and identify the critical mechanisms by addressing the following aims: (1) determine the mechanism underlying TNF induction of jagged-1 and the tip cell genes VEGFR2 and PDGF-B; (2) determine the mechanism(s) underlying jagged-1 induction of tip cell genes; and,(3) determine the mechanism underlying 3 integrin modulation of jagged-notch signaling. We will use a combination of in vitro angiogenesis models, including collagen gels, fibrin gels, aortic ring assays and embryoid bodies induced to sprout capillaries, as well as angiogenic sprouting into Matrigel plugs in vivo. Completion of this study will furnish us with adeeper understanding of jagged-notch interactions in angiogenesis and the role of TNF in coordinating these events. Lay Summary: The growth of new blood vessels is a critical process in development and cancer. The cells that line blooc vessels - the endothelial cells - talk to each other through cell surface molecules including a pair called notch and jagged. This study aims to understand why notch and jagged are so important for blood vesse development,. Completion of this study will not only provide us with fundamental knowledge about how the body works, but it will also provide us with new information that will help in the fight against cancer.

NOTCHL及其配体对于血管发育和血管生成至关重要，如 当这些基因在小鼠中删除时观察到胚胎致死性。虽然Notch信号传导良好的特征 - 通过配体三角洲和锯齿状的“反向信号”直到最近才被认可，它 在脉管系统中的作用是完全未知的。我们发现炎症介质TNF诱导 内皮细胞（EC）中的Agged-1表达，此外，诱导与血管生成相关的基因 IP细胞表型。此外，锯齿状参与双向信号传导，有助于建立尖端和 芽中的树干细胞表型。通过Notch锯齿状信号诱导Bhlhtranscrions 因子HESR1，以及随后调节其靶基因VEGFR2。锯齿状也发出信号电池 自主到核诱导与尖端细胞表型相关的基因，例如Vegfr2 和PDGF-B，并促进发芽。另外，TNF诱导0^3的表达，从而加强这些表达 通过与树干细胞中的Notch信号协同作用来发散表型。 TNF最初阻止发芽，都在 体外和体内，但一旦去除，发芽就会增加，这表明TNF“ Primes” EC。我们的 因此，初步数据使我们提出了以下假设： 协调血管生成的发作与急性炎症的分辨率。我们将检验这个假设 并通过解决以下目的来确定关键机制：（1）确定机制 锯齿状1和尖端细胞基因VEGFR2和PDGF-B的基础TNF诱导； （2）确定 尖端细胞基因诱导的JAGGED-1的机制； （3）确定基础机制 3锯齿状信号传导的整合素调制。我们将使用体外血管生成模型的组合， 包括胶原蛋白凝胶，纤维蛋白凝胶，主动脉环测定和诱发发芽毛细血管的胚胎物体，如 以及血管生成发芽到体内的矩阵塞。这项研究的完成将为我们提供Adeeper 理解锯齿状 - - 诺之间在血管生成中的相互作用以及TNF在协调这些事件中的作用。 摘要： 新血管的生长是发育和癌症的关键过程。蓝色的细胞 血管 - 内皮细胞 - 通过细胞表面分子相互交流，包括一对称为 缺口和锯齿状。这项研究旨在了解为什么Notch和Jagged对于血管如此重要 发展，。这项研究的完成不仅将为我们提供有关如何如何 身体工作，但它还将为我们提供有助于抗癌的新信息。