The Epstein Laboratory studies cardiovascular development, the genetics of congenital heart disease and cardiovascular regenerative and stem cell biology. The lab has a long-standing interest in congenital heart defects involving the outflow tract of the heart, the role of neural crest, the epicardium and the second heart field. More recent areas of focus include the cardiac inflow tract and the pulmonary veins and the origin of anomalous pulmonary venous return.
Other areas of interest include the factors and genes involved in progressive lineage restriction of cardiac progenitor cells and the role of epigenetics in progenitor cell expansion and differentiation. The lab is also interested in the implications of these studies for the development of new therapies for adult cardiovascular disorders including heart failure and arrhythmia. Specific projects have focused on the role of Notch and Wnt in cardiac progenitors, semaphorin signaling in the developing vasculature, the function of a novel homeobox gene Hopx and histone deacetylases in stem cells and the heart, and the role of the type I Neurofibromatosis gene (Nf1) in mouse and zebrafish cardiac development.
The Nf1flox/-;Tie2-Cre mice were produced from two crosses:
Cross 1: Nf1+/- X Tie2-Cre
Cross 2: Cross 1 X Nf1flox/flox
Tie2-Cre mice express Cre in endothelial cells and in the hematopoietic lineage.
Tie2-Cre efficiently recombined the floxed NF1 allele in most hematopoietic cells. Before 3 months of age mice appeared healthy and active. Some offspring from the cross to generate Nf1flox/-;Tie2-Cre mice died at mid-gestation of heart defects.
After identifying and characterizing the zebrafish orthologues (nf1a and nf1b) of the human neurofibromatosis gene NF1, morpholino antisense oligonucleotides were used to inhibit expression of these orthologues in zebrafish embryos in which endothelial cells were marked by expression of cytoplasmic enhanced green fluorescent protein. Cardiovascular and vascular patterning defects were greater with knockdown of nf1a than nf1b, suggesting that nf1a may play a more prominent role in cardiovascular development.