Penn Cardiovascular Institute Research Directory

Description of CVI Expertise

Scientific Director, Cardiovascular Institute
Chair, Department of Cell and Developmental Biology

CVI Program Unit Administrator:
Cardiovascular Development / Congenital Heart Disease

Research Interests
Transcriptional regulation of cardiac development and function using mouse models

Key Words: Cardiac development, Neural crest, Transcription, Hypertrophy, Pax, Neurofibromatosis.

The Epstein Lab studies molecular mechanisms of neural crest and cardiac development, with a particular interest in applying lessons learned from developmental models to the understanding and therapy of adult diseases. One area of interest relates to the role of the Pax3 transcription factor in neural crest cells. Neural crest can differentiate into a multitude of cell types including nerve, bone, vascular smooth muscle and melanocytes. Defects in neural crest, and mutations in Pax3, can lead to common forms of congenital heart disease. We have used mouse models to elucidate a molecular cascade involved in cardiac neural crest migration and differentiation, implicating members of the BMP, Notch, Semaphorin, myocardin and T-box families in this process. This work has direct relevance to the understanding of the genetic basis of congenital heart disease.

We have also used neural crest as a model of stem cell biology, and we have identified adult neural crest stem cells that reside in the hair follicle and give rise to regenerating melanocytes. Here, Pax3 plays a critical role both in determining cell-fate specification, and also in maintaining the undifferentiated stem cell phenotype until external signals, including induced by Wnt signals, trigger changes in transcriptional complexes and melanocyte differentiation.

Our studies have implicated important interactions between neural crest and other cell types, including vascular endothelium. We have discovered a novel member of the Plexin/Semaphorin family, PlexinD1, expressed by endothelial cells that is required for normal cardiovascular patterning. We have also demonstrated a critical endothelial function for the product of the type 1 Neurofibromatosis gene (NF1), which is a tumor suppressor gene mutated in von Recklinghausen Neurofibromatosis, a disease characterized by neural crest tumors and cardiovascular defects. This work has led to the appreciation for Ras signaling in epithelial-mesenchymal transformation in the heart and suggests that a common mechanism of cardiovascular defects in a series of childhood disorders, including Noonan’s syndrome and NF1. We are also using zebrafish models to exploit the ease of evaluation of the developing vasculature in our NF1 and Plexin studies.

Application of the elucidation of embryonic programs to adult disease is best exemplified by our work with a novel homeodomain factor called HOP. HOP is expressed early in cardiac development, but also functions in adult cardiac hypertrophy, and it is significantly down-regulated in human heart failure. HOP functions in association with HDAC2, a member of the histone deacetylase chromatin remodeling family. We have shown that HDAC inhibitors are potent anti-hypertensive agents, and our ongoing work suggests that HDAC2 is a critical molecular target of HDAC inhibitors in the heart. Our work suggests that HOP and HDAC2 regulate the fetal gene program during development, and again in the setting of adult disease when the fetal program is reactivated. Evaluation of these adult mouse models of heart disease is facilitated by imaging, microsurgery and invasive hemodynamic and electrophysiologic techniques that we have developed or refined to mimic all of the diagnostic tools available to the human adult cardiologist allowing us to develop new therapeutic targets for congestive heart failure.



Lab Personnel:
Ashley Cohen
Karl Degenhardt
Kurt Engleka
Raj Jain
Denise Juhr
Jun Li
Feiyan Liu
Lauren Manderfield
Daniele Massera
Maria Mercedes
Arun Padmanabhan
Stacey Rentschler
Manvendra Singh
Nikhil Singh
Norifumi Takeda
Chinmay Trivedi
Qiaohong Wang
Wenting Zhu