Research Highlights
Our physician-scientists use a combination of human and animal genetic model systems to better understand the genetic mechanisms of congenital heart disease, with the ultimate aim of improving therapies and preventive strategies.
Paul Grossfeld, M.D.
In Dr. Paul Grossfeld’s laboratory, scientists use genetically engineered mouse models to study how loss of ETS-1 causes congenital heart defects. Specifically, his lab has found that conditional deletion of ETS-1 in the neural crest causes ventricular septal defects, the most common congenital heart defect in Jacobsen syndrome, through a cell-autonomous mechanism. In collaboration with Dr. Alexey Terskikh, the team has also generated neural crest cells from patients with mutations in the ETS-1 gene and congenital heart defects. These studies have shown that patients with ETS-1 mutations and congenital heart defects have impaired neural crest cell migration, paralleling observations in ETS-1 knockout mice.
The lab’s current focus is on identifying the gene regulatory pathways involving ETS-1 in neural crest cells, which may lead to the identification of future therapeutic targets. Through a collaboration with Dr. Marianne Bronner and Dr. Shuyi Nie, Dr. Grossfeld’s lab has also developed an animal model for hypoplastic left heart syndrome (HLHS). Preliminary studies have identified a putative signaling pathway affected by the loss of ETS-1 and suggest that the HLHS phenotype can be rescued by grafting normal progenitor heart cells early in development. In addition to the neural crest, Dr. Grossfeld’s lab is studying the role of the endocardium in normal heart development and how loss of the ETS-1 gene may affect endocardial function and contribute to HLHS.
Dr. Grossfeld has also extended his studies to understanding the genetic basis of intellectual disability and behavioral problems. This work has led to the identification of several disease-causing genes, which have provided the basis for gene-based therapeutic clinical trials. In addition, Dr. Grossfeld serves as the cardiology consultant for U.S.A. Volleyball, helping develop a comprehensive screening program for athletes.
Francesca Briganti, Ph.D.
The Briganti Lab focuses on better understanding human tissue-specific post-transcriptional regulation of gene expression and developing mechanism-based therapeutics. The lab’s overall strategy is to study the function of regulatory genes and how their deregulation contributes to human disease.
Its specific approach is to understand the molecular mechanisms by which disease-causing mutations alter gene function and lead to human disease. The guiding hypothesis is that a detailed understanding of the relationship between a gene’s molecular function and disease mechanism will enable the development of first-in-class, personalized therapeutic strategies that target disease mechanisms rather than manage symptoms independently of disease etiology.