Intercellular Signaling in Cardiovascular Development and Disease

Intercellular signals in cardiovascular development and disease. We are interested in the molecular mechanisms that regulate cardiovascular development, homeostasis and disease. The early mammalian heart is a tube with an outer myocardial layer and an inner endocardium, separated by an extracellular matrix, the cardiac jelly. We and others have shown that the endocardium is a crucial source of patterning signals that regulate heart valve and chamber/ventricular development. The signaling function of the endocardium is exemplified by the NOTCH pathway, which is active in the endocardium and generates signals able to regulate a variety of cellular processes in the endocardium and in surrounding tissues, such as endocardial epithelial-mesenchyme transition, cardiomyocyte proliferation and differentiation, and coronary vessel development.

We are currently studying how NOTCH interacts with other signals during chamber development and cardiomyopathy. To this end, we have carried out an exome analysis of two familial pedigrees with cardiomyopathy, identified potentially pathogenic SNPs co-segregating with one NOTCH mutation of interest, and generated the corresponding genetically modified mouse models. We are currently analyzing the phenotypes of compound mutants, and of downstream NOTCH effector mutants (Gpr126), using a variety of techniques. We have also generated genetically modified mouse models for two sarcomere genes (MYBPC3 and ACTC1), in which specific mutations cause cardiomyopathies with mixed phenotypes (LVNC and HCM), to ascertain the molecular mechanism underlying these mixed phenotypes and uncover the genetic heterogeneity of cardiomyopathies.

We are also studying the genetic bases of bicuspid aortic valve (BAV) formation and the regulatory mechanisms controlling valve mesenchyme proliferation and differentiation. To this end, we have generated genetically modified mouse models for a variety of genes, and are in the beginning of the analysis of the mutant phenotypes. Upstream of NOTCH signaling there are enzymes like USP8 (ubiquitin-specific protease 8), crucial for signaling regulation of NOTCH and interacting pathways (Nrg1/ErbB2, VEGF-VEGFR2). We have generated conditional models for endocardium and myocardium, and are currently studying their mutant phenotypes, and conducting imaging analysis of cardiac development.

Lastly, we have carried out ATAC-seq with embryonic endocardial cells to identify the NOTCH-dependent gene regulatory landscape.

Selected candidate students will get involved in projects related with chamber development and cardiomyopathy and NOTCH signaling regulation.

For further reading: https://www.ncbi.nlm.nih.gov/pubmed/?term=de+la+pompa+jl