Descrizione del progetto
Il tumore del colon-retto può derivare da un eccesso di zelo
La riparazione dei tessuti è regolata da una complessa interazione tra sistema immunitario, tessuto leso e microbiota. A complicare ulteriormente le cose, l’infiammazione può svolgere un ruolo positivo o negativo. I meccanismi molecolari alla base delle interazioni sono ampiamente sconosciuti. La malattia infiammatoria intestinale e il tumore del colon-retto forniscono un’opportunità per esaminare le relazioni tra infiammazione, immunità, microbiota, riparazione dei tessuti e malfunzionamento delle vie di segnalazione. Il progetto REpAIR, finanziato dall’UE, sta studiando l’interleuchina-22 (IL-22) e il suo inibitore in tali processi patologici. L’IL-22, prodotta dalle cellule immunitarie, agisce sulle cellule epiteliali intestinali per modulare la composizione del microbiota e incentivare la rigenerazione tissutale. Tuttavia, essa può anche promuovere l’infiammazione cronica e il cancro. I risultati faranno luce su come le stesse vie possano condurre a una risposta di riparazione fisiologica o alla malattia, suggerendo terapie mirate per le malattie immunitarie e il cancro.
Obiettivo
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.
Campo scientifico
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesclinical medicineoncologycolorectal cancer
- natural sciencesbiological sciencesgeneticsRNA
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
20251 Hamburg
Germania