Using a systems biology approach our previous work has obtained insight into intracellular events and functional pathways in models of experimental PD and thereby identified inadequate or suppressed cellular stress responses (CSR) in mesothelial cells exposed to PDF as a novel pathomechanism in PD.
In our search for interventions for improving the CSR we identified the dipeptide alanyl-glutamine (Ala-Gln) as a promising cytoprotective additive to PDF. Current findings, so far, clearly support a specific role of Ala-Gln supplementation on the restoration of cytoprotective responses during PDF exposure, suggested by proteomic analysis of involved biological processes, which might be mediated by altered O-GlcNAcylation.
The overall goal of the CDL-MSRPD is to:
- facilitate introduction of novel PDFs for improving the CSR in PD
- by using hypotheses generating systems biology (WP1)
- combining a clinical sample repository (PD-BASE biobank) together
- with experimental testing of candidate mechanisms and compounds (WP2)
First-use-in man studies of Ala-Gln addition to PDF have yielded unique sample material, which will be further investigated using our proteomics platform. To this end we developed an enrichment approach that is capable of detecting subtle changes in protein abundances in PD effluents. On the basis of the established biobank, WP1 will combine orthogonal omics analyses and bioinformatic exploration to provide complementary information on activated stress responses, focusing on molecular signatures of the CSR on the level of biological processes, exploiting information on protein modification or transcriptional regulation in the context of clinical phenotypes. Direct comparison between technologies (cross-omics) at the level of individual gene products and proteins will provide additional insight into specific pathogenic processes and allow linking these processes to clinical subgroups and onsets on PD therapy.
We identified global O-GlcNAcylation as a first potential hub for the mode of action of Ala-Gln. This highly conserved cellular mechanism, which represents a rapid yet sustained molecular switch might be a central node for regulation of the CSR under PDF exposure conditions On the basis of previously generated in-vitro and in-vivo models, the impact and controllability of O-GlcNAcylation as well as the molecular targets of this environmental sensor will be investigated under PDF conditions combined with Ala-Gln in WP2.