Press Release

05.10.2020

DFG/ANR grant approval

In the approved DFG funded grant a German/French consortium led by Prof. Silke Meiners from the Comprehensive Pneumology Center/Institute of Lung Biology (iLBD) aims to explore the alternative proteasome complexes containing the proteasome activator PA200 as a new therapeutic target for IPF treatment.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no effective therapies beyond lung transplantation. Novel therapeutic approaches based on a mechanistic understanding of IPF development are thus urgently needed. The pathogenesis of IPF involves aberrant wound healing in response to continuous or repeated damage of the alveolar epithelium and subsequent activation of myofibroblasts. These activated myofibroblasts are key drivers for fibrosis as they produce excessive extracellular matrix proteins which deposition then contributes to impaired lung function and finally death in IPF patients. Dysregulation of the proteasome system – a central gatekeeper of protein homeostasis - is emerging as a novel pathomechanism for IPF. While application of catalytic proteasome inhibitors is hampered due to their toxic side effects, proteasome function might be modulated more specifically by interference with defined proteasome complexes. The proposed project aims to explore the role and regulation of the alternative proteasome complexes containing the proteasome activator PA200.

Recently published data from the Meiners lab revealed upregulation of PA200 in IPF lung tissue in activated myofibroblasts and unraveled PA200 to function as a negative regulator of myofibroblast differentiation. As PA200 has been proposed to be involved in the degradation of acetylated histones and chromatin remodeling, it is tempting to speculate that PA200 inducedchromatin remodelingmay contribute to IPF disease pathogenesis. To test this hypothesis, the project combines the translational expertise of the groups of Jürgen Behr from the university clinics of the Ludwigs-Maximilians Universität and Silke Meiners at the Comprehensive Pneumology Center in Munich with the unique expertise of Marie-Pierre Bousquet at the Institute of Pharmacology and Structural Biology in Toulouse on mass-spec based analysis of proteasome complexes. The scientists will investigate the regulation of PA200 in cells and ex vivo tissue of IPF patients in detail. Development of novel genetically engineered cell lines will allow depletion, mutation or activation of PA200 in fibroblasts and these tools will be combined with unbiased omic analysis and novel methods of the Bousquet lab for isolation and quantitative analysis of PA200/proteasome complexes and their substrates. This work will thereby decipher the molecular function of PA200/proteasome complexes in myofibroblast differentiation with a particular focus on chromatin remodeling. Moreover, using an in vitro drug screening approach, the consortium aims to find novel lead compounds that specifically inhibit PA200/proteasome complexes which might then prove useful for therapeutic targeting of PA200 in IPF pathogenesis