The long-term objectives of this proposal are to understand the genetic control of a specific subpopulation of endocardium, the pro-valve endocardial cells (PVECs), and determine their role in valve formation. During embryogenesis, NFATd expression is restricted to the endocardium and its expression is accentuated in the PVECs (endocardial cells that do NOT undergo mesenchymal transformation during the formation of cardiac valves). These observations suggest that a focus on NFATd regulation may provide unique insights into the transcriptional program orchestrating pro-valve endocardial development and valve formation. Having recently identified a 243 bp sequence within the first intron of NFATd that serves as a PVEC specific transcriptional enhancer required for accentuation of NFATd gene expression and having determined that a conserved 58 bp sequence within this enhancer region functions as a critical cis-regulatory element, controlling both the intensity and specificity of NFATd expression in the PVEC population, we hypothesized that this NFATd enhancer region defines an enhanceosome that plays a critical role in the regulation of NFATd expression essential for normal PVEC development and valve formation. Therefore, we propose to 1) Determine the molecular components and interactions required for activation of the PVEC-specific NFATd transcriptional enhancing complex using a novel enodardial cell line for gel shift, DNA affinity purification and mass psectrometry, 2) Define the in vivo role of the PVEC enhanceosome in PVEC development and valve formation utilizing a cre-loxp based dual-genetic mouse model for sequential analysis of enhanceosome suppression and activation of NFATd expression, and 3) Delineate the in vivo role of the PVEC endocardial subpopulation by spatiotemporal ablation of these cells using bigenic cre-/loxp, puAtk conditional genetic ablator mouse line. This work will define critical regulatory mechanisms required for heart valve development and will inform novel tissue-regeneration remedies for valve degeneration. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL078881-01A2
Application #
7145969
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Schramm, Charlene A
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2006-07-01
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$344,250
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Wu, Bingruo; Wang, Yidong; Xiao, Feng et al. (2017) Developmental Mechanisms of Aortic Valve Malformation and Disease. Annu Rev Physiol 79:21-41
Wang, Yidong; Wu, Bingruo; Farrar, Emily et al. (2017) Notch-Tnf signalling is required for development and homeostasis of arterial valves. Eur Heart J 38:675-686
Sung, Derek C; Bowen, Caitlin J; Vaidya, Kiran A et al. (2016) Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves. Arterioscler Thromb Vasc Biol 36:1627-37
Yang, Jin; Zeini, Miriam; Lin, Chieh-Yu et al. (2014) Epicardial calcineurin-NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development. Cardiovasc Res 101:120-9
Chamberlain, Alyssa A; Lin, Mingyan; Lister, Rolanda L et al. (2014) DNA methylation is developmentally regulated for genes essential for cardiogenesis. J Am Heart Assoc 3:e000976
Wu, Bingruo; Baldwin, H Scott; Zhou, Bin (2013) Nfatc1 directs the endocardial progenitor cells to make heart valve primordium. Trends Cardiovasc Med 23:294-300
Wang, Yidong; Wu, Bingruo; Chamberlain, Alyssa A et al. (2013) Endocardial to myocardial notch-wnt-bmp axis regulates early heart valve development. PLoS One 8:e60244
Zhang, Zheng; Zhou, Bin (2013) Accelerated coronary angiogenesis by vegfr1-knockout endocardial cells. PLoS One 8:e70570
Cai, Xiaoqiang; Zhang, Weijia; Hu, Jun et al. (2013) Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis. Development 140:3176-87
Wu, Bingruo; Zhang, Zheng; Lui, Wendy et al. (2012) Endocardial cells form the coronary arteries by angiogenesis through myocardial-endocardial VEGF signaling. Cell 151:1083-96

Showing the most recent 10 out of 15 publications