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ANR funded project

Innovation biomédicale (DS0404) 2014
Projet PARIS-IPF

Protease-activated Receptor-2 and its agonist serine proteases in idiopathic pulmonary fibrosis

Pulmonary fibrosis constitutes the end-stage of a broad range of heterogeneous diseases characterized by the destruction of pulmonary parenchyma and extracellular matrix deposition in the interstitial and alveolar spaces. Idiopathic pulmonary fibrosis (IPF) is the most frequent fibrotic diffuse parenchymal lung disease. Its prognosis is devastating, and there are currently no therapeutic options available. By contrast, in cryptogenic organizing pneumonia (COP), fibrosis is reversible spontaneously or under corticosteroids treatment. We recently showed that protease-activated receptor (PAR)-2, a cell surface receptor activated by proteolytic cleavage, is instrumental in pulmonary fibrosis. PAR-2 belongs to the superfamily ofa G-protein coupled receptors (GPCR). Its activation by proteolytic cleavage induces transmembrane signaling to intracellular G proteins linked to its COOH, intracellular extremity. The activated G proteins in turn impact on a substantial network of signaling pathways with functional consequences are of crucial importance in pathophysiology. In mammals, only a finite number of serine proteases (agonists) is able to activate PAR-2. Based on our data, showing a crucial role for PAR-2 in the progression of pulmonary fibrosis, we hypothesize that targeting PAR-2, the majpor endogenous PAR-2 activating proteases, and/or the downstream signaling pathways subsequent to PAR-2 activation will limit pulmonary fibrosis. In the current PARIS-IPF proposal, we propose to address this question by employing integrated approaches, ranging from analysis of human material to cell and animal models. In patient material, we will identify and compare the major endogenous PAR-2 activating proteases in IPF and COP. We will characterize their action ex vivo and in vitro. Using high throughput technology based on peptide kinome array, we propose to establish the kinome profile of the major PAR-2 activating proteases on normal and fibrotic fibroblasts, to validate their importance ex vivo in IPF and COP, and to elucidate the involvement of PAR-2 in the signaling pathways activated. Finally, we will assess the effect of genetic and pharmacological modulation of the targets identified in a murine model of pulmonary fibrosis. Identifying the common and divergent mechanisms underlying irreversible or reversible fibrosis in IPF of COP respectively will provide important insights and potential therapeutic targets which could be used to treat IPF.

Partners

INSERM INSERM UMR 1152

UMR_S933 INSERM INSERM DR P6

ANR grant: 250 100 euros
Beginning and duration: janvier 2015 - 48 mois

 

ANR Programme: Innovation biomédicale (DS0404) 2014

Project ID: ANR-14-CE15-0010

Project coordinator:
Madame Keren Borensztajn (INSERM UMR 1152)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.