Tyrosine kinase inhibition in pulmonary hypertension: experimental and clinical studies

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The project aims to investigate the role of tyrosine kinases (TK) in the pathobiology of pulmonary vascular diseases. In this project we will investigate the role of different tyrosine kinases in experimental and clinical pulmonary hypertension. Experimentally, we will employ established models for pulmonary hypertension (PH). Elaborate screening tools like laser assisted microdissection of vascular compartments followed by quantitative RT-PCR will be employed to gain more insight in expression pattern of RTKs in plexiform lesions, neointima, media and adventitia. Interventional experiments will show, whether tyrosine kinase inhibitors with different inhibitory profiles can reverse pulmonary vascular remodeling. In addition, transgenic mouse models, like PDGF receptor (PDGFR)-beta overexpressing mice or discoidin domain receptor (DDR) knockout mice, will be employed to pinpoint the role of different tyrosine kinases and dependent pathways in PH. Along the same line, we will investigate the expression of RTK and the downstream signaling cascades in human lung tissue from patients with PAH. The overall goal is to alleviate abnormal proliferation of (peri-)vascular cells by means of tyrosine kinase inhibition and to achieve reversal of the structural remodeling in the diseased lung vasculature by interference with tyrosine kinase dependent signaling („Reverse Remodeling“).