Heart Valve Morphogenesis

Using pharmacological inhibitors, tissue-specific gene disruption and conventional gene knockout in mice, we have demonstrated that calcineurin/NFAT signaling plays two sequential and critical roles in the initiation and propagation of heart valve morphogenesis. The initiation of valve formation requires myocardial NFAT to repress the expression of VEGF (vascular endothelial growth factor). We are studying how VEGF interacts with NFAT signaling during valve formation, and the molecular mechanism of NFAT-mediated VEGF repression.

Myocardial Development and Coronary Angiogenesis

Using tissue-specific gene knockout technology in mice, we have generated mouse lines deficient in endocardial transcription factors or chromatin remodeling molecules. One of the mutant lines develops abnormal myocardial growth and trabeculation. These observations suggest that endocardial factors are required for myocardial development. We are studying the molecular and cellular mechanisms of how endocardial cells control myocardial development. Furthermore, we have generated several mouse lines lacking myocardial or epicardial transcription factors or chromatin remodeling molecules. These mice fail to form mature myocardium, interventricular septum or coronary arteries. We are investigating the molecular basis of these cardiac and vascular defects.

Patterning of Cardiac Outflow Tract and Great Arteries

Using compound gene mutations in mice, we have demonstrated that Pbx gene family members (homeodomain proto-oncogenes) are essential for the patterning of cardiac outflow tracts and great arteries. We are investigating the molecular pathways controlled by Pbx genes during cardiac development.

Cardiomyopathy and Vascular injury

We have generated a mouse model of restrictive cardiomyopathy and a mouse model that allows us to study the signaling events during the repair process following vascular injury such as balloon angioplasty. These models are directly relevant to a specific type of human congestive heart failure and the restenosis following angioplasty and stenting seen in clinical cardiology. We are investigating the pathogenesis of cardiomyopathy and the mechanisms of vascular restenosis following injury.