Dissection of the genetic and molecular underpinnings of heart valve development

• Applicant: Professor Dr. Steffen Just
• Subject Area: Cardiology, Angiology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262392696

Defective development of heart valves accounts for in 20-30% of congenital malformations. However, in most cases, the underlying genetic and molecular causes have not been identified yet. There is increasing evidence that the regulatory mechanisms governing normal heart valve development also contribute to human valve pathology. We recently have shown that a novel Protein Kinase D2 (PKD2) dependent signalling pathway is involved in the regulation of cardiac valve development by controlling HDA5-Notch1 signaling specifically in endocardial cells of the atrioventricular canal (AVC). In the proposed research we now aim (1) to characterize the role of the PKD2-HDAC5-NOTCH1 signaling cascade on the initiation and progression of endothelial-to-mesenchymal transition (EMT) of endothelial cells in vitro and in vivo. Furthermore, we aim (2) to dissect the genetic and molecular pathology of the novel zebrafish heart valve mutant tailback. Finally, we aim (3) to identify the heart-specific tailback-interactome using yeast two hybrid technology and to in vivo characterize these tailback interacting proteins by overexpression and knock-down studies in zebrafish. In summary, the proposed research will ultimately help to further dissect the genetic etiology and pathophysiology of human heart valve diseases, which is essential for the development of more specific treatment strategies.

• DFG Programme: Research Grants