Congenital heart valve defects are among the most common cardiac developmental anomalies and can lead to valve degeneration with surgical replacement later in life. The underlying causes of congenital heart valve defects are not well known, but altered expression of extracellular matrix (ECM) components and remodeling enzymes are associated with developmental as well as degenerative valve disease. A candidate transcription factor in the control of heart valve maturation is Tbx20, a T-box transcriptional regulatory protein that is expressed during valvulogenesis. Early in heart development, Tbx20 promotes myocardial proliferation and inhibits maturation. We hypothesize that Tbx20 similarly promotes valve cell proliferation and inhibits maturation by decreasing chondroitin sulfate proteoglycan (CSPG) and increasing MMP expression. Experiments in transgenic mice and cultured chicken valve progenitor cells will be used to examine the normal functions of Tbx20 in the regulation of valvulogenesis as well as to determine the consequences of altered Tbx20 activity on heart valve structure and function.
The aims of the research are to: 1. Manipulate Tbx20 function during heart valve formation in vivo to determine effects of altered Tbx20 activity on heart valve cell proliferation, ECM organization and remodeling. 2. Identify proximal effects of Tbx20 on cell proliferation, ECM organization and gene expression in cultured endocardial cushion cells. 3. Introduce expression of matrix remodeling enzymes ADAMTS4 and MMP13, in vivo to assess the effects of compromised ECM on valve structure and function. The accomplishment of the proposed research will establish regulatory hierarchies in the development of complex heart valve structures. The long-term goal of these studies is to identify critical regulatory interactions that control normal and abnormal valve development with potential applications for adult valve disease mechanisms. Heart valve functional defects occur in at least 5 million individuals in the United States and valve disease has become steadily more common over the last 20 years. There is increasing evidence that valve structural genes expressed during embryonic development are also affected during adult disease. The increased understanding of the process of valve development has potential clinical significance in the identification of congenital heart disease genes as well as in the development of therapies for valve degeneration in adults.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082716-04
Application #
7617207
Study Section
Special Emphasis Panel (ZRG1-CVS-E (02))
Program Officer
Schramm, Charlene A
Project Start
2006-07-01
Project End
2010-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$364,125
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Fang, Ming; Xiang, Fu-Li; Braitsch, Caitlin M et al. (2016) Epicardium-derived fibroblasts in heart development and disease. J Mol Cell Cardiol 91:23-7
Xiang, Fu-Li; Guo, Minzhe; Yutzey, Katherine E (2016) Overexpression of Tbx20 in Adult Cardiomyocytes Promotes Proliferation and Improves Cardiac Function After Myocardial Infarction. Circulation 133:1081-92
Wirrig, Elaine E; Yutzey, Katherine E (2014) Conserved transcriptional regulatory mechanisms in aortic valve development and disease. Arterioscler Thromb Vasc Biol 34:737-41
Chakraborty, Santanu; Sengupta, Arunima; Yutzey, Katherine E (2013) Tbx20 promotes cardiomyocyte proliferation and persistence of fetal characteristics in adult mouse hearts. J Mol Cell Cardiol 62:203-13
Braitsch, Caitlin M; Yutzey, Katherine E (2013) Transcriptional Control of Cell Lineage Development in Epicardium-Derived Cells. J Dev Biol 1:92-111
Yutzey, Katherine E (2013) A twist of proepicardial fate. Circ Res 113:1106-8
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Braitsch, Caitlin M; Combs, Michelle D; Quaggin, Susan E et al. (2012) Pod1/Tcf21 is regulated by retinoic acid signaling and inhibits differentiation of epicardium-derived cells into smooth muscle in the developing heart. Dev Biol 368:345-57

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