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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.
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Principal Investigator

Manolis Pasparakis (Prof.)

Host institution

UNIVERSITAET ZU KOELN

Address

Albertus Magnus Platz
50931 Koeln

Germany

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 500 000

Principal Investigator

Manolis Pasparakis (Prof.)

Administrative Contact

Silke Rohn (Mrs.)

Beneficiaries (1)

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UNIVERSITAET ZU KOELN

Germany

EU Contribution

€ 2 500 000

Project information

Grant agreement ID: 323040

Status

Closed project

  • Start date

    1 May 2013

  • End date

    30 April 2018

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 2 500 000

  • EU contribution

    € 2 500 000

Hosted by:

UNIVERSITAET ZU KOELN

Germany