Notch signaling in cardiovascular morphogenesis

描述（由申请人提供）：本修订后的申请主要关注Notch信号在心血管发展中的作用。我们实验室发表的和初步的数据表明，Notch在血管平滑肌发育过程中在心脏神经嵴细胞中起着关键的细胞自主作用，在心脏形态发生过程中也起着重要作用。由内皮Jagged1介导的Notch激活刺激未分化间质向平滑肌分化，最终成为血管平滑肌。我们已经开始阐明的这一途径，为血管是如何通过内皮管周围平滑肌的凝结和分化形成提供了重要的线索。我们已经证明，在这个过程中的缺陷可以导致可预测的形式的先天性心脏病涉及心脏的流出道。此外，Notch信号在第二心野的心肌细胞祖细胞中是必需的。未发表的数据表明，心脏前体的规范和扩张受到Notch的影响，当Notch信号受到干扰时，心脏心室和流出道缺陷就会出现。在本提案中，我们验证了Notch介导心脏和血管形成过程中细胞间通讯的关键方面的假设。修订后的申请涉及较少的遗传杂交，比最初提交的申请更机械。第三个目标已经被完全取代，使我们能够测试一个详细的模型，该模型将Notch在第二心脏场中的作用与影响心脏瓣膜和流出道形成的细胞-细胞通信和信号通路结合起来。具体目的如下：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。在jagged介导的Notch激活过程中，Notch通过激活Jagged1表达介导正反馈循环的假设将被验证。2)确定Notch在第二心野中的作用。我们将对第二心野祖细胞Notch信号的功能获得和功能丧失进行研究。3)探讨第二心野Notch活性影响心内膜缓冲和流出道发育的机制。涉及Jagged1， Notch, Fgf8， Bmp4和MRTF-B的信号级联将被检查。

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 Unpublished data indicates that specification and expansion of cardiac precursors are affected by Notch, and that cardiac ventricular and outflow tract defects arise when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