We are interested in the endocardium, the internal endothelial lining of the heart, as it is a source of instructive signals that regulate patterning, growth and differentiation of adjacent cardiac tissues to give rise to the mature ventricles, valves and coronary vessels. We use a combination of genetically modified mice, omics and imaging technologies to discover how genes and pathways regulate developmental processes that may go awry and cause disease. We also use human tissue and cells to validate our findings in cardiovascular disease.

Our efforts are centered on the role of NOTCH and interacting signaling pathways in cardiac valves and chamber development and disease. During mouse cardiac development NOTCH activity is restricted to the endocardium (see: Know more). We are studying how Notch signaling in the valves interacts with other pathways or genes to cause valve dysmorphology. Recently, we have identified a genetic signature predictive of aortic valve calcification (PMID: 33044885), and we aim to validate and expand this signature in a large population of calcific disease patients using single cell RNA-seq of peripheral blood cells. We have also recently identified a set of regulatory regions and candidate genes dependent on NOTCH during valvulogenesis in mice by ATAC-seq, RNA-seq and secretome experiments (PMID: 31249105).

Endocardial-to-myocardial signaling is essential for ventricular chamber development (see: Know more). We study how different pathways regulate the cellular and molecular mechanisms involved in the formation of trabeculae, which are myocardial protrusions covered by endocardium, necessary for embryonic nourishment. NOTCH signaling disruption impairs the process of compaction, that occurs following trabeculation, causing left ventricular non-compaction cardiomyopathy (LVNC). Our murine and hiPSC models show that LVNC is due to defective myocardial maturation and persistent cardiomyocyte proliferation. Exome analysis of families has identified a set of genes potentially interacting with NOTCH to cause LVNC. We are characterizing the phenotype of the corresponding mutant mice, and the biochemical interactions among the gene products involved. Mutations in some sarcomere genes cause both LVNC and HCM, and we are currently investigating the genetic and mechanistic bases of these apparently disparate cardiomyopathies.