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Spatio-Temporal Regulation of Inflammation and Tissue Regeneration: Studying the immune system - tissue - microbiota communication to develop targeted therapies for immune-mediated diseases and cancer

Project description

Colorectal cancer may result from too much of a good thing

Tissue repair is regulated by a complex interplay among the immune system, injured tissue and microbiota. To make matters more complicated, inflammation can play a positive or a negative role. The molecular mechanisms underlying the interactions are largely unknown. Inflammatory bowel disease and colorectal cancer provide an opportunity to investigate the relationships among inflammation, immunity, microbiota, tissue repair and signalling pathways gone awry. The EU-funded project REpAIR is studying interleukin-22 (IL-22) and its inhibitor in these disease processes. IL-22, produced by immune cells, acts on intestinal epithelial cells to modulate microbiota composition and promote tissue regeneration. However, it can also promote chronic inflammation and cancer. Outcomes will shed light on how the same pathways can lead to either a physiological repair response or to disease and point to targeted therapies for immune-related diseases and cancer.

Objective

Inflammation is fundamental to promote tissue regeneration upon injury, and in turn, the resolution of the immune response. Physiological tissue regeneration depends on fine-tuned interaction between the immune system, the tissue, and the microbiota. However, the complex communication between these three components and the molecules that mediate it are unclear. Understanding this is fundamental to prevent immune-mediated diseases and even cancer. This is particularly important at mucosal surfaces, where continued regeneration occurs. Therefore, we hypothesize that inflammatory bowel disease (IBD) and colorectal cancer (CRC) are a consequence of a miscommunication between these components.
Interleukin-22 (IL-22) is one key orchestrator of this communication: It is produced by immune cells and by acting on intestinal epithelial cells, it modulates the composition of the microbiota and promotes tissue regeneration. However, IL-22 can also promote both chronic inflammation and cancer. Exactly what regulates these paradoxical effects remains unclear. Of note, there is an endogenous inhibitor of IL-22, namely IL-22 binding protein (IL-22BP), which blocks IL-22 activity. We hypothesize that a misguided spatio-temporal regulation of the IL-22 – IL-22BP axis is the cause of pathogenic effects of IL-22.
In particular, we will analyse: (i) the location, and the functional and molecular heterogeneity; (ii) the origin and fate of IL-22 and IL-22BP producing immune cells; and (iii) the role of the microbiota in regulating them. To this end, we will use new transgenic and gnotobiotic mouse models, single cell RNA sequencing and human samples.
In short, by studying the IL-22 - IL-22BP axis, we will understand how the complex interactions between the immune system, the tissue, and the microbiota lead to either physiological or pathological tissue regeneration. This will provide the basis for therapies controlling inflammation and tissue regeneration in a spatio-temporal manner.

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

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ERC-COG - Consolidator Grant

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Call for proposal

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(opens in new window) ERC-2019-COG

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Host institution

UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 356 125,00
Address
Martinistrasse 52
20251 Hamburg
Germany

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Region
Hamburg Hamburg Hamburg
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 356 125,00

Beneficiaries (2)

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