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 Unpublished data indicates that specification and expansion of cardiac precursors are affected by Notch, and that cardiac ventricular and outflow tract defects arise when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

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095634-03
Application #
8206560
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2010-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$396,000
Indirect Cost
$148,500
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Engleka, Kurt A; Manderfield, Lauren J; Brust, Rachael D et al. (2012) Islet1 derivatives in the heart are of both neural crest and second heart field origin. Circ Res 110:922-6
de la Pompa, Jose Luis; Epstein, Jonathan A (2012) Coordinating tissue interactions: Notch signaling in cardiac development and disease. Dev Cell 22:244-54
Manderfield, Lauren J; High, Frances A; Engleka, Kurt A et al. (2012) Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation 125:314-23
Rentschler, Stacey; Epstein, Jonathan A (2011) Kicking the epicardium up a notch. Circ Res 108:6-8
Rentschler, Stacey; Harris, Brett S; Kuznekoff, Laura et al. (2011) Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways. J Clin Invest 121:525-33
Jain, Rajan; Engleka, Kurt A; Rentschler, Stacey L et al. (2011) Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves. J Clin Invest 121:422-30
Li, Deqiang; Epstein, Jonathan A (2011) Micro-managing myocyte mitosis. Circ Res 109:611-3