The early cardiac cushions are located in the atrioventricular canal (AV) of the embryonic heart. These cushions are populated with mesenchymal cells and are the primordia of future cardiac valves and membranous septa. Valvular defects are among the most common and deleterious of all cardiac malformations. Importantly, significant progress has been made in delineating the molecular mechanisms that regulate the early steps of cushion formation, as numerous genes have been identified. However, little is known about how these cushions differentiate into valve leaflets. This is due, in part, to the fact that there is not an adequate model system to study later stages of valve development. The present research proposes to change this with the development of a new collagen tube scaffold system in which cushion anlagen matures into valve tissue. This new model expands upon our recently developed tissue engineering system of culturing embryonic cardiac myocytes. Chick stage 22 AV cushions grown within the lumen of spontaneously-contracting tube cultures were found to undergo morphological changes that model the later stages of valve development. Consistent and promising initial results indicate that valve leaflet formation in the tube model is dependent on the presence of cardiac myocytes. This proposal seeks to investigate the fidelity and utility of the tube model to recapitulate in vivo leaflet formation. The proposed experiments are designed to test the molecular, cellular, and tissue mechanisms that regulate the morphogenesis of AV valves in the tube model. The central hypothesis is that the tube culturing system can be used to investigate the roles that myocardial tissues and fluid forces play in the development of cardiac valve leaflets. Since valve formation is of significant biomedical interest, a model system that mimics late stages of in vivo valve formation will be essential in determining the roles that individual and collective biochemical and physical factors play in valve formation.
Two specific aims have been developed to address the hypothesis of this application:
Aim1 : Test the ability of the tube model system to accurately reproduce the role of the myocardium in the later stages of valvulogenesis:
Aim 2 : Test the hypothesis that fluid flow can drive the maturation of AV valves.
| Evans, Heather J; Edwards, Laura; Goodwin, Richard L (2007) Conserved C-terminal domains of mCenp-F (LEK1) regulate subcellular localization and mitotic checkpoint delay. Exp Cell Res 313:2427-37 |
