Human genetics

We have an active human genetics effort based in the Cardiovascular Clinical Genetics Center, the Brigham Genomic Medicine group and the national Undiagnosed Diseases Network. In addition to traditional genomic approaches to gene discovery in disease families, we also have developed a Next Generation Phenotyping platform in our ambulatory clinics that is designed to test and validate new technologies bringing cell biology or physiology to the bedside. Many human diseases have arisen as clusters of unrelated disorders that share only some gross cardiac phenotype. We have begun to stratify these disorders and understand the mechanism using non-cardiac phenotypes through approaches as diverse as facial recognition, wearables and short term drug responses.

Zebrafish as tools for drug discovery

Our lab is highly interested in developing systematic understanding of the relationship between genes and environment using high throughput, phenotype-driven genetic and chemical screens in the zebrafish. Our interest ranges from the most primitive cellular behaviors to more complex pathophysiological processes. Taking advantage of the scalability and rapid development of the zebrafish, we have used these startegies to study gene-gene and gene-environment interactions in development and in disease biology. Recently we used this approach to identify chemical suppressors of different genetic causes of heart failure, and we are now using the initial ‘hit’ compounds to explore new therapies for these conditions. We are now expanding these efforts to undertake ‘co-clinical’ modeling of specific disease genes with a view to rapid pathway insights and capturing real time insight for individual patients.

We have also developed a systematic approaches to predicting gene-phenotype relationships based on iterative in silico modeling and in vivo validation. These studies have demonstrated that efficient prioritization in zebrafish can accelerate the pace of gene function discovery.

Cellular communication

Proper embryogenesis and organ function is critically dependent on finely-tuned intra- and intercellular communications. Our lab is devoted to further unravel the mechanisms via which populations of cells within the cardiovascular system propagate signals, interact with each other and coordinate their activities. To test our current hypotheses, we have developed several state-of-the-art imaging techniques to visualize a range of signals at cellular or sub-cellular resolution in the developing zebrafish. We have used these techniques to understand the in vivo dynamics of the non-canonical Wnt pathway and the integration of complex signals from traditional developmental pathways. Primary areas of focus include, but are not restricted to cardiomyocyte-cardiomyocyte, endocardial-myocardial interactions and the neurovascular interactome.