Work package 1 - Identification of common pathways that influence disease outcome and response to treatment and infection
We will adopt two approaches, the genomic approach responsible for identifying the FOXO3 pathway; and a bottom up approach that has identified de-regulation of autophagy as a prime candidate. The work performed will include the analysis of pathways and their genomic background that influence the intensity and persistence of severe autoimmune and inflammatory diseases. It will characterize the mechanisms through which these operate in cellular models derived from patients with autoimmune disorders segregated by sex and age. The pathway analysis will validate results from WP02 on discovery of proteomic markers of disease activity or clinical outcome in patients with immune-mediated disease and the results will inform experiments executed in WP03 on ageing.
Description of the tasksWP01 will build up on Partner UCAM’s expertise in identifying genomic pathways that influence the intensity and persistence of severe autoimmune and inflammatory diseases, and on characterizing molecular mechanisms responsible. Thus, a polymorphism in the FOXO3 promoter was found that affected transcription and had a powerful influence on the outcome of Crohn’s Disease. Subset analysis of genome-wide association study (GWAS) data has the potential to identify genetic variants associated with disease outcome rather than presentation. We will apply the same strategy to ANCA-associated vasculitis. This disease has been carefully selected to maximize the opportunity for discovering new genetic polymorphisms that influence disease outcome and of characterizing their effects. To facilitate this, we will exploit novel and exceptionally efficient ways of generating induced pluripotent stem cells (iPSCs) to create a panel of cell lines from healthy individuals of the appropriate genotype and from patients with extreme (severe/mild) disease phenotypes. The group will use macrophages and dendritic cells differentiated from these iPSCs to extend the analysis of the FOXO3 polymorphism to autophagy, a cellular pathway it controls, and related genes. This will be done using state of the art techniques optimized by Partner MUW, facilitated by the development of novel peptide reagents for manipulating autophagy which will be undertaken by Partner EMC.
Objectives of this work package
The research plan in this Work Package is designed to identify common pathways that influence disease outcome and response to treatment and infection in autoimmune and inflammatory diseases.