Project Details
Projekt
The role of the proteasome activator PA200 in myofibroblast differentiation and fibrosis of the lung
Subject Area
Pneumology, Thoracic Surgery
Biochemistry
Biochemistry
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 446339549
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. In the proposed project, we aim to explore the role and regulation of the alternative proteasome complexes containing the proteasome activator PA200.PA200 has been proposed to be involved in the degradation of acetylated histones and chromatin remodeling. The exact cellular function of PA200, however, is not understood yet. Disease related regulation or dysfunction of PA200 has not been observed so far. Our own published data revealed upregulation of PA200 in IPF lung tissue in activated myofibroblasts and unraveled PA200 to function as a negative regulator of myofibroblast differentiation. Our unpublished data indicate that PA200 regulates chromatin remodeling which may contribute to IPF disease pathogenesis.To test this hypothesis, the project combines the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. We will first investigate the regulation of PA200 in cells and ex vivo tissue of IPF patients in detail. Development of novel genetically engineered cell lines will then allow depletion, mutation or activation of PA200 in fibroblasts and these tools will be combined with unbiased omic analyses (RNA, DNA and protein) and novel methods of the Bousquet lab for isolation and quantitative analysis of PA200/proteasome complexes and their substrates. We will thereby decipher the molecular function of PA200/proteasome complexes in myofibroblast differentiation with a particular focus on chromatin remodeling. Moreover, with our in vitro drug screening approach, we aim to find novel lead compounds that specifically inhibit PA200/proteasome complexes which might then prove useful for therapeutic targeting of PA200 in IPF pathogenesis.
DFG Programme
Research Grants
International Connection
France
Partner Organisation
Agence Nationale de la Recherche / The French National Research Agency
Cooperation Partner
Dr. Marie-Pierre Bousquet
