Alveolar epithelial endoplasmic reticulum (ER)-stress in Idiopathic Pulmonary Fibrosis - identification of molecular trigger events and role in fibrotic repair

• Antragsteller: Professor Dr. Andreas Günther
• Fachliche Zuordnung: Pneumologie,Thoraxchirurgie
• Förderung: Förderung von 2010 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 166385523

Chronic epithelial injury has been proposed to underly Idiopathic Pulmonary Fibrosis (IPF), a life-threatening disease with an average survival time of 2-3 years. Our group recently discovered severe, pro-apoptotic ER-stress in alveolar type II cells (AECII). As one underlying reason, we identified defective post-translational processing of surfactant proteins (SP)-B and C, with intracellular accumulation of unprocessed SP as a result of the downregulation of the lysosomal proteases napsin A and cathepsin H. We now aim to: i) proof causality and precisely describe molecular mechanisms underlying the induction of ER stress in vitro and in vivo (overexpression of cleavage resistant variants of proSP-B in vitro, generation of transgenic mice with AECII specific, inducible expression of shRNAs against napsin A and cathepsin H), ii) characterize the transcriptional regulation of cathepsin H and napsin A under conditions of health and disease (reporter gene and silencing assays, chromatin immunoprecipitation studies), iii) to evaluate new therapeutic approaches in IPF, which are centered on the prevention of protein misfolding (application or overexpression of chaperones) or the blockade of the pro-apoptotic, ER-stress derived, transcription factor CHOP.

• DFG-Verfahren: Sachbeihilfen