Notch Signaling in Vascular Development and Homeostasis

血管发育和稳态中的Notch信号传导

• 批准号: 7598978
• 负责人: M. LUISA IRUELA-ARISPE
• 金额: $ 38.2万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7598978
• 关键词: Ablation; Adult; Biological; Birth; Blood Vessels; Caliber; Cardiac; Cells; Cessation of life; Congenital Heart Defects; Data; Defect; Development; Embryo; Endothelial Cells; Endothelium; Event; Excision; Exhibits; Experimental Designs; Gene Deletion; Generations; Genetic; Goals; Heart; Hemorrhage; Homeostasis; In Vitro; Knock-out; Knockout Mice; Ligands; Link; Literature; Maintenance; Maps; Mediating; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Notch Signaling Pathway; Pathology; Pathway interactions; Pattern; Phenotype; Publishing; Research Personnel; Role; Series; Severities; Shunt Device; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Staging; Testing; Time; Tissues; Vascular System; Venous; angiogenesis; base; effective therapy; insight; interest; jagged1 protein; mouse model; mutant; notch protein; novel; programs; receptor; repaired; research study

DESCRIPTION (provided by applicant): Our long-term goal is to gain a comprehensive understanding of the molecular programs required for the formation of blood vessels. A combination of genetic and cell biological data has established a critical role for Notch signaling in vascular morphogenesis. However, concrete mechanistic insight into Notch's cellular effects in vascular development and differentiation is still far reached. Deletion of Notch 1 results in early embryonic lethality (E.9.5) with multiple defects, including alterations in the heart and vessels. To gain a detailed understanding of Notch1 effects in the vascular compartment, we have generated a mouse model with endothelial-cell specific deletion of Notch1 using a Cre-lox strategy. As in the full deletion, this mouse dies between E9.5-10.5 from collapse of the vascular system, but does not exhibit somitic mesodermal defects and cardiac features seen after global inactivation. Mutant embryos displayed congenital aortic branch defects, reduced aortic lumen, aneurisms, arterial-venous shunts and deregulated vascular branching. We also generated an inducible Cre-lox mouse and subsequently deleted Notch at later developmental time points. Interestingly, ablation of Notch at E10.5 results in hemorrhage and lethality at E13.5. Furthermore, deletion of Notch at E15.5 also leads to multiple hemorrhagic events with lethality at birth. These findings support and expand our understanding of Notch and further highlight the exquisite requirement of this signaling pathway during vascular stabilization and maturation at later time-points. Our current focus is to gain a mechanistic understanding of Notch function at the cellular level and to establish the molecular links of these effects downstream of the Notch signaling pathway. By using a variety of mouse models and in vitro approaches, we propose: (1) to gain a mechanistic understanding of Notch1's effects during vascular development, (2) to explore the contribution of Notch1 in the homeostasis of adult vessels and in pathological conditions, and (3) to evaluate the contribution of Notch-ligand Jagged1 during development. The molecular mapping of vascular morphogenesis is critical to understanding how vessels are formed. Many of the events that take place during development are recapitulated in situations of neoangiogenesis and vascular repair in the adult. Thus, this information is central to the generation of novel and more effective therapies that will enable manipulation of vascular function during pathological conditions.

描述（由申请人提供）：我们的长期目标是全面了解血管形成所需的分子程序。遗传和细胞生物学数据的结合已经确定了 Notch 信号在血管形态发生中的关键作用。然而，对于Notch在血管发育和分化中的细胞效应的具体机制了解还很遥远。 Notch 1 的缺失会导致早期胚胎致死 (E.9.5)，并伴有多种缺陷，包括心脏和血管的改变。为了详细了解 Notch1 在血管室中的作用，我们使用 Cre-lox 策略生成了内皮细胞特异性删除 Notch1 的小鼠模型。与完全缺失中一样，该小鼠在 E9.5-10.5 之间因血管系统崩溃而死亡，但没有表现出整体失活后观察到的体节中胚层缺陷和心脏特征。突变胚胎表现出先天性主动脉分支缺陷、主动脉腔缩小、动脉瘤、动静脉分流和血管分支失调。我们还生成了可诱导的 Cre-lox 小鼠，并随后在后来的发育时间点删除了 Notch。有趣的是，E10.5 处的 Notch 消融会导致 E13.5 处出血和致死。此外，E15.5位点Notch的缺失也会导致多起出生时致命的出血事件。这些发现支持并扩展了我们对Notch的理解，并进一步强调了该信号通路在稍后时间点的血管稳定和成熟过程中的严格要求。我们目前的重点是在细胞水平上获得对 Notch 功能的机制理解，并建立 Notch 信号通路下游这些效应的分子联系。通过使用各种小鼠模型和体外方法，我们建议：（1）从机制上了解Notch1在血管发育过程中的作用，（2）探索Notch1在成体血管稳态和病理条件下的贡献，以及（3）评估Notch配体Jagged1在发育过程中的贡献。血管形态发生的分子图谱对于理解血管如何形成至关重要。发育过程中发生的许多事件在成人的新血管生成和血管修复的情况下得到重演。因此，这些信息对于产生新颖且更有效的疗法至关重要，这些疗法将能够在病理条件下操纵血管功能。