The TBX5 transcription factor plays a critical role in establishment of cardiac structure, and TBX5 mutations cause human congenital heart disease. We have demonstrated that Tbx5 plays a critical role in chick proepicardial cell migration during embryonic establishment of the epicardium and coronary vasculature. In human embryonic tissue, TBX5 expression is high in the epicardium and coronary vascular wall but is inactivated in the subepicardial cells delaminating from the epicardium to form coronary vessels. Preliminary data also suggest that Tbx5 activity in the proepicardium upregulates expression of the Ets-2, a transcription factor that has also been implicated in coronary vasculogenesis. We then hypothesize that Tbx5-dependent transcriptional circuits involving Ets-2 play critical roles in proepicardial, epicardial and coronary vessel development during embryogenesis. Furthermore, because we have shown that Tbx5 activities is re-expressed in adult human and murine bone-marrow derived stem cells differentiating into angioblasts, we hypothesize that Tbx5 can modify adult endothelial precursor cell differentiation, potentially via Ets-2 activation, and may thereby participate in cell mediated revascularization of the adult ischemic heart. In this application, we propose to utilize chick and mouse experimental models: (1) To determine the contributions of Tbx5 to establishment of the eppicardium and coronary vessels; (2) To define the impact of Tbx5 on Ets-2 expression in the proepicardial derivatives and the contribution of Ets-2 to Tbx5 signaling during epicardial development and coronary vasculogenesis; (3) To determine the role of Tbx5 expression during angioblastic differentiation of adult mammalian bone marrow derived stem cells. These studies will highlight critical transcriptional regulators of coronary vascular progenitor cell behavior and will both shed light on fundamental mechanisms that underlie the development of the coronary vasculature as well as foster novel targets to promote the revascularization of cardiac tissue in individuals with ischemic cardiomyopathies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080663-04
Application #
7386745
Study Section
Special Emphasis Panel (ZRG1-CDD (01))
Program Officer
Schramm, Charlene A
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$398,236
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Diman, Nata Y S-G; Brooks, Gabriel; Kruithof, Boudewijn P T et al. (2014) Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis. Circ Res 115:834-44
Zhang, Jun; Sawyer, Janet K; Marshall, Stephanie M et al. (2014) Cholesterol esters (CE) derived from hepatic sterol O-acyltransferase 2 (SOAT2) are associated with more atherosclerosis than CE from intestinal SOAT2. Circ Res 115:826-33
Kim, Luke; Devereux, Richard B; Basson, Craig T (2011) Impact of genetic insights into mendelian disease on cardiovascular clinical practice. Circulation 123:544-50
Wolf, Michael; Basson, Craig T (2010) The molecular genetics of congenital heart disease: a review of recent developments. Curr Opin Cardiol 25:192-7
Hatcher, Cathy J; Basson, Craig T (2009) Specification of the cardiac conduction system by transcription factors. Circ Res 105:620-30
McDermott, Deborah A; Hatcher, Cathy J; Basson, Craig T (2008) Atrial Fibrillation and Other Clinical Manifestations of Altered TBX5 Dosage in Typical Holt-Oram Syndrome. Circ Res 103:e96
Lin, Angela E; Basson, Craig T; Goldmuntz, Elizabeth et al. (2008) Adults with genetic syndromes and cardiovascular abnormalities: clinical history and management. Genet Med 10:469-94
Bee, Katharine J; Wilkes, David; Devereux, Richard B et al. (2006) Structural and functional genetic disorders of the great vessels and outflow tracts. Ann N Y Acad Sci 1085:256-69