Notch signaling in cardiovascular morphogenesis

心血管形态发生中的Notch信号传导

• 批准号: 8011429
• 负责人: Jonathan A. Epstein
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011429
• 关键词: Address; Adult; Affect; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Communication; Cells; Childhood; Communication; Data; Defect; Development; Feedback; Genes; Genetic Crosses; Heart; Heart Diseases; Heart Valves; Human; Maintenance; Mediating; Mesenchyme; Modeling; Morphogenesis; Muscle Development; Mutation; Myocardium; Natural regeneration; Neural Crest; Neural Crest Cell; Pathway interactions; Physical condensation; Process; Publishing; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Testing; Tissues; Tube; Undifferentiated; Vascular Smooth Muscle; Ventricular; Work; congenital heart disorder; loss of function; notch protein; progenitor; public health relevance

DESCRIPTION (provided by applicant): This revised application focuses on the role of Notch signaling in cardiovascular development. Published and preliminary data from our lab have demonstrated a critical, cell autonomous role for Notch in cardiac neural crest cells during vascular smooth muscle development and additional vital roles during cardiac morphogenesis. Notch activation, mediated by endothelial Jagged1, stimulates smooth muscle differentiation of undifferentiated mesenchyme fated to become vascular smooth muscle. This pathway, which we have begun to elucidate, provides important clues as to how a blood vessel forms by condensation and differentiation of smooth muscle around an endothelial tube. We have shown that defects in this process can result in predictable forms of congenital heart disease involving the outflow tract of the heart. Furthermore, Notch signaling is required in cardiomyocyte progenitors of the second heart field. Unpublished data indicates that specification and expansion of cardiac precursors are affected by Notch, and that cardiac ventricular and outflow tract defects arise when Notch signaling is perturbed. In this proposal, we test the hypothesis that Notch mediates critical aspects of cell-cell communication during cardiac and vascular formation. The revised application involves fewer genetic crosses is more mechanistic than the original submission. The third aim has been completely replaced to allow us tol test a detailed model that integrates the role of Notch in the second heart field with cell-cell communication and signaling pathways that impact cardiac valve and outflow tract formation. The proposal involves the following specific aims: 1) To elucidate the role of Jagged1 and Notch in endothelial-smooth muscle communication during vascular development. The hypothesis that Notch mediates a positive feedback loop by activating Jagged1 expression upon Jagged-mediated Notch activation will be tested. 2) To determine the role of Notch in the second heart field. We will perform both gain and loss of function for Notch signaling in second heart field progenitors. 3) To examine the mechanism by which Notch activity in the second heart field affects endocardial cushion and outflow tract development. A signaling cascade involving Jagged1, Notch, Fgf8, Bmp4 and MRTF-B will be examined. PUBLIC HEALTH RELEVANCE: The proposed work addresses fundamental questions relevant to an understanding of how the cardiovascular system forms and how we might be able to regenerate new blood vessels and new functional myocardium. The role of Jagged1 and Notch are known to be important in human cardiac disease since both adult and pediatric heart disorders are known to be associated with mutations in the genes encoding these molecules.

描述（由申请人提供）：本修订后的申请重点关注 Notch 信号传导在心血管发育中的作用。我们实验室已发表的初步数据表明，Notch 在血管平滑肌发育过程中的心脏神经嵴细胞中发挥着关键的细胞自主作用，并且在心脏形态发生过程中发挥着其他重要作用。由内皮 Jagged1 介导的 Notch 激活刺激未分化间充质的平滑肌分化，最终成为血管平滑肌。我们已经开始阐明的这条途径，为了解血管如何通过内皮管周围平滑肌的凝结和分化而形成提供了重要线索。我们已经证明，这一过程中的缺陷可能导致可预测的涉及心脏流出道的先天性心脏病。此外，第二心脏区域的心肌细胞祖细胞需要Notch信号传导。未发表的数据表明，心脏前体细胞的规范和扩张受到Notch的影响，并且当Notch信号传导受到干扰时，会出现心室和流出道缺陷。在本提案中，我们测试了这样的假设：Notch 在心脏和血管形成过程中介导细胞间通讯的关键方面。修改后的申请涉及更少的基因杂交，比原始提交的申请更加机械化。第三个目标已被完全取代，以便我们能够测试一个详细的模型，该模型将 Notch 在第二心脏区域中的作用与影响心脏瓣膜和流出道形成的细胞间通讯和信号通路相结合。该提案涉及以下具体目标：1）阐明Jagged1和Notch在血管发育过程中内皮-平滑肌通讯中的作用。 Notch 通过在 Jagged 介导的 Notch 激活后激活 Jagged1 表达来介导正反馈循环的假设将得到测试。 2)确定Notch在第二心脏区域中的作用。我们将在第二心脏区祖细胞中执行Notch信号传导功能的获得和丧失。 3) 研究第二心区Notch活动影响心内膜垫和流出道发育的机制。将检查涉及 Jagged1、Notch、Fgf8、Bmp4 和 MRTF-B 的信号级联。 公共健康相关性：拟议的工作解决了与了解心血管系统如何形成以及我们如何能够再生新血管和新功能心肌相关的基本问题。众所周知，Jagged1 和 Notch 在人类心脏病中发挥着重要作用，因为成人和儿童心脏病都与编码这些分子的基因突变有关。