Notch signaling in cardiovascular morphogenesis

描述（由申请人提供）：本修订申请的重点是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已经证明了Notch在血管平滑肌发育期间在心脏神经嵴细胞中的关键细胞自主作用以及在心脏形态发生期间的其他重要作用。Notch激活，由内皮锯齿1介导，刺激未分化间充质的平滑肌分化，注定成为血管平滑肌。我们已经开始阐明的这一途径为血管如何通过内皮管周围平滑肌的凝聚和分化形成提供了重要线索。我们已经证明，在这个过程中的缺陷，可导致可预测的形式的先天性心脏病，涉及流出道的心脏。此外，Notch信号传导在第二心脏区域的心肌细胞祖细胞中是必需的。未发表的数据表明，规范和扩张的心脏前体细胞的Notch的影响，心脏心室和流出道缺陷时，Notch信号被扰乱。在这个建议中，我们测试的假设，Notch介导的心脏和血管形成过程中的细胞间通讯的关键方面。修改后的申请涉及更少的遗传杂交，比原来的提交更机械。第三个目标已被完全取代，使我们能够测试一个详细的模型，该模型将Notch在第二心脏领域中的作用与影响心脏瓣膜和流出道形成的细胞-细胞通讯和信号传导途径相结合。本研究的主要目的是：1）阐明Jagged 1和Notch在血管发育过程中内皮-平滑肌通讯中的作用。将测试Notch通过在Jagged介导的Notch激活后激活Jagged 1表达来介导正反馈环的假设。2)确定Notch在第二心脏领域中的作用。我们将在第二心脏区域祖细胞中进行Notch信号传导功能的获得和丧失。3)研究第二心脏区域的Notch活动影响内膜垫和流出道发育的机制。将检查涉及Jagged 1、Notch、Fgf 8、Bmp 4和MRTF-B的信号级联。 公共卫生相关性：拟议的工作解决了与理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有关的基本问题。已知Jagged 1和Notch在人类心脏病中的作用很重要，因为已知成人和儿童心脏病都与编码这些分子的基因突变有关。

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 Unpublished data indicates that specification and expansion of cardiac precursors are affected by Notch, and that cardiac ventricular and outflow tract defects arise when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.