Genetic background of endothelial cell pathopyhsiology in pulmonary hypertension.

• Applicant: Dr. Nils Nickel
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 217553304

Endothelial cells (ECs) play a major role in the pathophysiology of idiopathic pulmonary arterial hypertension (IPAH). The underlying ECs dysfunction remains unknown. So far a genetic background of IPAH is well recognized. Germline mutations of TGF--proteins are linked to the onset of IPAH. In a recently published manuscript it was shown that besides TGF- germline mutations, acquired somatic mutations could contribute to the pathobiology of IPAH. The background of this project is the genetic comparison of ECs from IPAH lungs and stem cell induced ECs from skin fibroblasts of the same patient. Our hypotheses are: (1) during disease development, lung-specific somatic mutations contribute to disease progress. Those mutations are found exclusively in pulmonary ECs. (2) Pulmonary ECs from IPAH patients will show mutations that are not found in iPSC-ECs derived from skin fibroblasts of the same patient. These mutations have strong effects of ECs cell cycle, proliferation and apoptosis. (3) Genetic re-engineering of these genetic mutations will restore a normal ECs phenotype. Investigation of the genetic basis of ECs dysfunction in IPAH could provide important insights into mechanistic backgrounds of IPAH pathophysiology. These results could lead to a novel understanding of IPAH as a chronic proliferative disease and could provide ground for new diagnostic approaches and therapies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Marlene Rabinovitch