Cardiovascular defects associated with the formation and remodeling of endocardial cushion tissue accounts for a large proportion of congenital heart disease in the United States each year [1.2]. The molecular mechanisms integrating the processes of proliferation, differentiation, and apoptosis for proper remodeling of the tubular heart to form the four- chambered organ is not clear. The complex processes associated with remodeling of endocardial cushion tissue into valvular structures involves multiple cell lineages of myocardial, endothelial, mesenchymal, neural crest, and epicardial origins. Remodeling events such as epithelial-to- mesenchymal transformation to cushion tissue and myocardialization in the outflow tract and atrioventricular canal are the result of a precise coordination of these processes. The retinoid X-receptor alpha knockout (RXRalpha-KO) mouse model shows considerable promise at clarifying these relationships and aiding in the determination of the causes of congenital heart defects. At embryonic day (E) 13.5, RXRalpha-KO embryos display a spectrum of endocardial fusion tissue and ventricular chamber malformations analogous to human congenital heart defects [3.5]. Preliminary evidence indicates there is a reduced proliferation and increased apoptosis in RXRalpha-KO embryonic hearts. Moreover,, in RXRalpha-KO embryos, we found elevated levels of TGF-beta2 mRNA and protein in the heart. Thus, our hypothesis is that RXRalpha functions to integrate the processes of proliferation, differentiation, and apoptosis during remodeling of cushion tissue in the outflow tract, AV canal, and ventricular myocardium and that TGF-beta2 contributes to these processes in an RXRalpha-dependent manner.
The Specific Aims of this proposal are: 1) To test the hypothesis that epithelial-to-mesenchymal cell transformation in the conotruncal and atrioventricular cushions is RXRalpha-dependent. II) To determine the role of RXRalpha in the processes of proliferation and apoptosis during septation of the conotruncus and ventricular chambers. III) To test the hypothesis that disruption of RXRalpha expression during cardiogenesis results in cardiac defects that are TGFbeta2 dependent.
| Urban, Erich; Wakai, Ronald T (2012) Optical sensor position indicator for neonatal MEG. IEEE Trans Biomed Eng 59:255-62 |
| Hewett, Kenneth W; Norman, Lisa W; Sedmera, David et al. (2005) Knockout of the neural and heart expressed gene HF-1b results in apical deficits of ventricular structure and activation. Cardiovasc Res 67:548-60 |
| Sedmera, David; Reckova, Maria; DeAlmeida, Angela et al. (2003) Spatiotemporal pattern of commitment to slowed proliferation in the embryonic mouse heart indicates progressive differentiation of the cardiac conduction system. Anat Rec A Discov Mol Cell Evol Biol 274:773-7 |
| Kubalak, Steven W; Hutson, D Renee; Scott, Karen K et al. (2002) Elevated transforming growth factor beta2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor alpha knockout embryos. Development 129:733-46 |
