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Epithelial cells in inflammation

Objective

The cross talk between the host and the microbiota is believed to be the major determinant of health and disease in the gastrointestinal tract. Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the intestine with unclear aetiology. Deregulation of the cross talk between the intestinal microbiota and the host immune system is considered a main factor contributing to IBD. Genomic studies revealed associations of NOD2 and of genes regulating autophagy and ER stress with an increased risk for IBD. Mutations in these pathways compromise Paneth cell dependent epithelial antibacterial defences causing alterations in the intestinal microbiota, termed dysbiosis. However, mutations in NOD2 or autophagy genes are not sufficient to cause intestinal inflammation in humans or in mice, suggesting that dysbiosis by itself cannot cause inflammation but additional, as yet unidentified, factors are required to precipitate the pathogenesis of IBD in genetically susceptible individuals. Mouse model studies revealed that epithelial specific mutations sensitizing intestinal epithelial cells to apoptosis or necroptosis triggered spontaneous intestinal pathologies with many features of human IBD, including loss of Paneth cells, impaired epithelial antimicrobial defences and chronic intestinal inflammation. We hypothesize that pathways controlling programmed cell death critically contribute to the pathogenesis of IBD by acting on Paneth cells to regulate epithelial antibacterial defences and simultaneously regulating intestinal epithelial cell survival and the integrity of the epithelial barrier. The aims of this research proposal are: a) to dissect the pathways regulating Paneth cell death and the development of dysbiosis in the gut, and b) to elucidate the additional genetic or environmental factors regulating intestinal epithelial barrier integrity that are likely to synergise with Paneth cell dysfunction and dysbiosis to trigger chronic intestinal inflammation.

Call for proposal

ERC-2012-ADG_20120314
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Host institution

UNIVERSITAT ZU KOLN
Address
Albertus Magnus Platz
50931 Koln
Germany

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Activity type
Higher or Secondary Education Establishments
Administrative Contact
Silke Rohn (Mrs.)
Principal investigator
Manolis Pasparakis (Prof.)
EU contribution
€ 2 500 000

Beneficiaries (1)

UNIVERSITAT ZU KOLN
Germany
EU contribution
€ 2 500 000
Address
Albertus Magnus Platz
50931 Koln

See on map

Activity type
Higher or Secondary Education Establishments
Administrative Contact
Silke Rohn (Mrs.)
Principal investigator
Manolis Pasparakis (Prof.)