Diagnostic and prognostic biomarkers for inflammatory bowel disease (IBD-BIOM)
IBD-BIOM is a multidisciplinary consortium of leading academic and industrial SME researchers in inflammatory bowel disease, epigenetics, glycomics, glycoproteomics and activomics. The main aim of the project is to identify novel diagnostic and prognostic biomarkers and new targets for therapeutic intervention.
Genetic predisposition, environmental factors, nutrition and ethical background are acknowledged risk factors for IBD development. IBD GWAS studies identified innate immunity, autophagy and interleukin-23 receptor signalling pathways as important in pathogenesis of chronic gastrointestinal inflammation. In addition, IBD results from inappropriate response of immune system to microbial antigens, which is promoted by certain environment as well as genetic individual susceptibility. Recent GWAS study preformed by our partner from Genos identified 16 gene loci (Lauc et al. 2013 PLoS Genetics) involved in IgG glycosylation and 5 of them showed pleiotropy with IBD (Figure 1).
Figure 1. Five out of 16 GWAS loci relevant for IgG glycosylation show pleiotropy with inflammatory bowel disease (IBD).
Covalent addition of glycans to IgG represents an important mechanism in control of the immunoglobulin function converting this antibody from anti- to pro-inflammatory molecule (Figure 2). Zoldoš lab is interested if the aberrant promoter methylation in genes associating with IgG glycosylation and showing pleiotropy with IBD is the mechanism behind the aberrant IgG glycosylation playing role in IBD. The candidate genes are: the MGAT3 (glycosyltransferase), the IL6ST (signaling transporter of many cytokines), the IKZF1 (transcriptional regulator of lymphocite differentiation, a component of chromatin remodelling complexes), the BACH2 (transcription factor involved in differentiation, maturation and activation of B cells) and the LAMB1 (a member of glycoprotein family of extracellular matrix). DNA methylation analyses will be performed on whole blood, B cells isolated from whole blood and T cells isolated from inflamed bowel tissue of patients with ulcerative colitis and Crohn’s disease from two independent cohorts. Correlation study will be done for N-glycan and DNA methylation data in the very same patients from the both cohorts.
Figure 2. Imunoglobulin G (IgG) has a single glycosylation site on each heavy chain (Fc region). The alternative glycosylation change a function of IgG antibody: the addition of galactose and/or sialic acid on N-acetyl glucosamine transform IgG molecule from a proinflammatory to an anti-inflammatory antibody.
Type of funding scheme: Collaborative project – small or medium-scale focused research project – stage 2
Work programme topics: HEALTH.2012.2.4.5-2: Biomarkers and diagnostics for chronic inflammatory diseases of the joints and/or digestive system. FP7-HEALTH-2012-INNOVATION-1
EU FP7 Call: FP7-HEALTH-2012-INNOVATION-1
Host institution: Faculty of Science University of Zagreb
Coordinating person: Prof Jack Satsangi, PhD, University of Edinburgh, UK
EU Funding Total: 5,999,611.00 Eur
EU Funding UNI-ZG: 552,146.00 Eur
Detailed information: http://www.ibdbiom.eu/science/
Regional Potential project REGPOT-2012-2013-1:
Integrating research in molecular life sciences at the University of Zagreb (INTEGRA-LIFE)
INTEGRA-LIFE functionally integrates and reinforces the most promising research groups in glycoproteomics, epigenetics, genetic engineering, biochemistry and bioinformatics through collaboration with 13 eminent European partnering organisations.
Within the project the epigenetic group is exploring several important themes:
- epigenetic regulation of IgG glycosylation in model systems for B cells (hybridoma and lymphoblastoma) using CRISPR/Cas9-based tools for genome and epigenome editing (collaboration with Faculty of Pharmacy and Biochemistry of the University of Zagreb, Center for Proteomics Faculty of Medicine University of Rijeka, IGMM University of Edinburgh, and IARC Lyon)
- Promoter methylation analysis of candidate genes involved in testicular cancer
- Epigenetic regulation of HNF1A in HNF1A-MODY-subtype of diabetes using CRISPR/Cas9-based tools for epigenome editing
Type of funding scheme: SP4-Capacities; Coordination and support action; Support actions
Work programme topics:
EU FP7 Call: FP7-REGPOT-2012-2013-1
Host institution: University of Zagreb
Coordinating person: Prof Gordan Lauc, PhD, Faculty of Pharmacy and Biochemistry University of Zagreb
EU Funding UNI-ZG: 3,224,464.00 Eur
Detailed information: http://integralife.bioinfo.hr