Analyzing endothelial cell migration and factors affecting this migration
Very complex signaling pathway are necessary to guide endothelial cells into forming the specific vascular pattern during embryonic development, but also during growth, wound healing or during progression of diseases like cancer, stroke or arterio-venous malformations. To analyze the factors regulating the behavior of endothelial cells in healthy and disease conditions we are using zebrafish embryos, either with genetic defects of by pharmacologically impairing regulatory pathways. A main focus of these studies lies on endothelial migrations and the mechanisms of shunt formations between arteries and veins, specifically on the differentiation state and contribution each of these specialized vessels has. Live imaging of the endothelial cell behavior as well as molecular analysis of gene and protein expression (changes) will allow for new insights into which factors regulate correct or aberrant pattern formation and therefore will help to identify potential therapeutic interventions.
Zebrafish as a model for human congenital cardiovascular disease
Cardiovascular malformations are among the most common human congenital diseases. Most of these cardiovascular defects affect the heart outflow tract and the connecting aortic arch arteries (AA). These specialized regions of the cardiovascular system require complex tissue interactions to develop and specifically depend on the contribution of specialized neural crest cells. Therefore, disruptions in neural crest cell specification, migration or differentiation are involved in the manifestation of these cardiovascular malformations, with DiGeorge Syndrome being one prominent example. Even though multiple candidate genes have been associated with the syndrome, the mechanism and etiology of the disease itself are poorly understood. By using zebrafish mutants identified from a forward genetic screen, we will be able to analyze the behavior of individual endothelial cells in healthy and disease condition. We have isolated three mutants affecting AA development or maintenance and heart outflow tract remodeling, one of them specifically resembling the DiGeorge syndrome phenotypes. Detailed analysis, especially live imaging of cellular behavior during AA development and outflow tract remodeling in these mutant embryos will allow for new insights into the disease etiology.
Funding
North Rhine Westphalia Return Fellowship