Coronary artery disease accounts for 54% of all cardiovascular disease in the United States [1]. Understanding how coronary vessels develop is likely to uncover novel drug targets and therapeutic strategies useful in directing the repair or remodeling of coronary vessels in adults. Recent data from our laboratory has demonstrated that targeted deletion of the Type III Transforming Growth Factor 2 receptor (TGF2R3) results in embryonic death associated with failure of the formation or persistence of the coronary vessels while other vascular beds appear to develop normally. Experiments are proposed to identify how the loss of TGF2R3 results in the failure of coronary vessel development and to reveal the TGF2 signaling pathways that regulate epicardial cell differentiation. We will test 3 specific hypotheses. Hypothesis 1: TGF2R3 is required for proper epicardial differentiation. This will be tested by in vivo analysis of the epicardium and epicardial derivatives in wildtype, heterozygous Tgfbr3 null, and homozygous Tgfbr3 null animals. Hypothesis 2: TGF2R3 is required in the epicardium or myocardium for proper coronary vessel development. This will be tested by conditional deletion of Tgfbr3 in the epicardium and myocardium. Hypothesis 3: Specific TGF2 signaling pathways regulate epicardial cell differentiation. This will be tested in vitro in both explants and immortalized cells from wildtype, heterozygous Tgfbr3 null, and homozygous Tgfbr3 null animals The successful completion of the proposed experiments will yield significant insight into the role of Transforming Growth Factor 2 (TGF2) in coronary vessel development. The unique nature of the derivation of the coronary vessels and the significance of coronary vessel disease in humans makes the determination of the mechanisms behind TGF2R3 regulation of coronary vasculogenesis of high significance from both a basic science and clinical perspective. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL085708-01A2
Application #
7379859
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2008-02-01
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
1
Fiscal Year
2008
Total Cost
$380,388
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Clark, Cynthia R; Robinson, Jamille Y; Sanchez, Nora S et al. (2016) Common pathways regulate Type III TGFβ receptor-dependent cell invasion in epicardial and endocardial cells. Cell Signal 28:688-98
Doetschman, Thomas; Barnett, Joey V; Runyan, Raymond B et al. (2012) Transforming growth factor beta signaling in adult cardiovascular diseases and repair. Cell Tissue Res 347:203-23
Hill, Cynthia R; Sanchez, Nora S; Love, Joseph D et al. (2012) BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFβ receptor to promote invasion. Cell Signal 24:1012-22
Sanchez, Nora S; Barnett, Joey V (2012) TGFýý and BMP-2 regulate epicardial cell invasion via TGFýýR3 activation of the Par6/Smurf1/RhoA pathway. Cell Signal 24:539-48
Sanchez, Nora S; Hill, Cynthia R; Love, Joseph D et al. (2011) The cytoplasmic domain of TGFýýR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior. Dev Biol 358:331-43
Frieden, Leslie A; Townsend, Todd A; Vaught, David B et al. (2010) Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1. Dev Dyn 239:3226-34
Karunamuni, Ganga; Yang, Ke; Doughman, Yong Qiu et al. (2010) Expression of lymphatic markers during avian and mouse cardiogenesis. Anat Rec (Hoboken) 293:259-70
Craig, Evisabel A; Austin, Anita F; Vaillancourt, Richard R et al. (2010) TGFβ2-mediated production of hyaluronan is important for the induction of epicardial cell differentiation and invasion. Exp Cell Res 316:3397-405
Craig, Evisabel A; Parker, Patti; Austin, Anita F et al. (2010) Involvement of the MEKK1 signaling pathway in the regulation of epicardial cell behavior by hyaluronan. Cell Signal 22:968-76