IBDase

PROJECT CONCEPT: Identify the P/PI genes that are genetically and mechanistically linked to Inflammatory Bowel Disease.

STRATEGY: Apply a multi-step strategy to filter those P/PIs with highest impact on susceptibility and pathogenetic mechanisms in IBD.

• Initially, the complete set of genes will be scored based on information available in online databases and scientific literature.

• Selected P/PI genes will be genotyped in independent patient cohorts for polymorphism associations with IBD clinical phenotypes and known susceptibility genotypes.

• Expression of the IBD-associated genes will be analysed in clinical specimens from IBD patients as well as in cell and organ culture and IBD animal models. The role of the microflora is to be addressed in co-culture models in vitro as well as in animal models with targeted colonisation of the gut.

• Expression of the candidate genes and their allelic variants will be modulated in experimental models in vitro as well as in vivo in transgenic and KO animals, leading to substrate identification and a proposed molecular mechanism for their role in modulating the inflammatory response. These findings will provide a functional link to the genetic association with IBD. Independent experimental observations that suggest an involvement of particular P/PIs in mucosal inflammation may feed back to human genetic association studies.

• P/PIs that fulfil the criteria of having a plausible pathogenetic mechanism and demonstrating genetic associations in IBD will be validated within a high-throughput genetic diagnostic platform together with other, previously defined IBD-associated genes.

• Integration of all the available information will ultimately be used to select three genes for study as therapeutic targets in IBD.