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FRIPRO-Fri prosjektstøtte

Intestinal epithelial cells: Central coordinators in Inflammatory Bowel Disease and targets for treatment

Alternative title: Tarmepitelceller: Sentrale koordinatorer i inflammatorisk tarmsykdom (IBD) og mål for behandling.

Awarded: NOK 9.5 mill.

The main types of IBD, ulcerative colitis (UC) and Crohn’s disease (CD), are serious chronic conditions negatively affecting life, usually from a young age. A well-established hypothesis is that environmental and microbial triggers lead to an inappropriate immunological response in genetically susceptible individuals. There is great variation in symptoms, disease course and responses to treatments. Medications used for IBD vary from classic anti-inflammatory agents to antibodies and small molecules that more specifically target parts of the immune system. However, these interventions offer no cure and have unpredictable effects. Today, the aim of treatment is to reduce the inflammation, provide relief of symptoms and prevent relapse. Because UC and CD manifest as inflammatory diseases, most IBD research has focused on immune cell-mediated mechanisms. Intestinal epithelial cells (IECs) are probably significantly more central in gut inflammation than previously acknowledged. Still, there are few drugs directly targeting IECs in IBD, and we do not know whether drugs that have been developed to affect immune cells have negative or positive effects on epithelial functions. In this project, we use advanced 3D organoid technology to gain mechanistic understanding of the mode of action of approved and emerging IBD drugs on IECs, identify whether drugs designed against immune cell show adverse effects in IEC, and identify novel epithelial-targeted therapies. Organoids from patient-derived intestinal biopsies ("mini-guts") can be kept in long-term 3D cultures (colonoids from the large intestine and enteroids from the small intestine). Such ex vivo models are closer to actual disease biology than animal models and cancer cell lines that have been used previously in IBD research. The ambition for the project is to provide insights into IBD pathobiology and bring forward detailed mechanistic knowledge about the role of IECs in IBD that can facilitate precision medicine in IBD.

We hypothesize that intestinal epithelial cells (IECs) are significantly more central in gut inflammation than previously acknowledged and challenge the view that immune cells should be the main target for treatment for Inflammatory Bowel Diseases (IBD). Every IBD patient presents with a unique disease and treatment history, and their own hereditary and environmental backdrop. This IBD cohort heterogeneity can only be captured through combinatory analyses of clinical information and laboratory results from real-life biological material or patient-derived ex vivo models faithfully reproducing the heterogeneity. Therefore, the proposed project has a genuine translational approach focusing on systematic clinical observations in parallel with research on patient specific epithelial organoids (“mini-guts”) that can reproduce patient heterogeneity. We will perform state-of the art functional studies and evaluate approved and investigational IBD-drugs as treatment options targeting observed physical, biochemical, and immunological intestinal epithelial dysfunctions. Since research into IBD pathobiology has mainly focused on immune cell-mediated mechanisms there is very limited information about how the drugs commonly used in IBD affect epithelial functions in health and disease. The American Crohn’s & Colitis Foundation (ACCF) recently highlighted that “understanding the essential role of the intestinal epithelium in IBD is paramount, particularly since mucosa healing has become major endpoint in clinical management of patients”. The present project will directly answer important questions regarding IEC biology and meet challenges as stated by ACCF. The ambition for the project is to bring forward detailed mechanistic knowledge about the role of IECs in IBD that can facilitate precision medicine.

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FRIPRO-Fri prosjektstøtte

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