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 Unpublished data indicates that specification and expansion of cardiac precursors are affected by Notch, and that cardiac ventricular and outflow tract defects arise when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）：此修订后的申请专注于Notch信号在心血管发育中的作用。来自我们实验室的已发表和初步数据表明，在血管平滑肌发育过程中，Notch在心脏神经crest细胞中的关键细胞自主作用和心脏形态发生过程中的其他重要作用。由内皮锯齿状1介导的Notch激活刺激未分化的间充质的平滑肌分化，成为血管平滑肌。我们已经开始阐明的这一途径提供了重要的线索，即通过在内皮管周围平滑肌的缩合和分化血管形成如何形成。我们已经表明，在此过程中的缺陷可以导致可预测的先天性心脏病形式，涉及心脏的流出道。此外，第二心脏场的心肌祖细胞中需要凹槽信号传导。未发表的数据表明，心脏前体的规范和膨胀受Notch的影响，当缺口信号扰动时，心脏心室和流出道缺陷会出现。在此提案中，我们检验了以下假设，即在心脏和血管形成过程中，Notch介导了细胞 - 细胞通信的关键方面。修订后的应用涉及的遗传杂交比原始提交更具机械性。第三个目标已被完全替换，使我们可以测试一个详细的模型，该模型将Notch在第二心脏场中的作用与影响心脏瓣膜和流出道形成的细胞电池通信和信号通路。该提案涉及以下特定目的：1）阐明锯齿状1和缺口在血管发育过程中内皮平滑肌肉交流中的作用。 Notch通过激活锯齿状介导的Notch激活时激活Jagged1的表达来介导正反馈循环的假说将进行测试。 2）确定Notch在第二心脏场中的作用。我们将在第二心脏场祖细胞中对Notch信号传导的功能和功能丧失。 3）检查第二个心脏场中缺口活性影响心内膜垫和流出道的机制。将检查涉及JAGGED1，NOTCH，FGF8，BMP4和MRTF-B的信号级联反应。 公共卫生相关性：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性心肌有关的基本问题。众所周知，Jagged1和Notch的作用在人类心脏病中很重要，因为已知成人和小儿心脏病都与编码这些分子的基因中的突变有关。