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 Unpublished data indicates that specification and expansion of cardiac precursors are affected by Notch, and that cardiac ventricular and outflow tract defects arise when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