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Metaplasia as an adaptive response to chronic microbial infections

Descrizione del progetto

Uno sguardo più attento ai meccanismi dei tumori del tessuto epiteliale

L’infezione gastrica cronica correlata all’helicobacter pylori è un esempio del modo in cui l’infezione batterica cronica può dare origine a tumori umani del tessuto epiteliale. Nonostante si manifesti con frequenza, i meccanismi esatti del cancro epiteliale indotto da microbi rimangono ignoti. Tuttavia, alcune recenti ricerche suggeriscono che la fase precancerosa della metaplasia gastrica intestinale sia una forma di difesa antimicrobica adattiva di un organismo. Il progetto MADMICS, finanziato dall’UE, indagherà su tale ipotesi per gettare nuova luce sul ruolo delle infezioni batteriche nello sviluppo del cancro umano. MADMICS analizzerà inoltre i cambiamenti mutazionali ed epigenetici connessi alla metaplasia gastrica intestinale e approfondirà un nuovo metodo di prevenzione del cancro.

Obiettivo

The epithelial surfaces are frequently affected by harsh encounters, thus it is not surprising that most cancers originate here. Several chronic bacterial infections have been implicated in human cancers, with Helicobacter pylori (Hp) representing the paradigm of a cancer-inducing bacterium. The gastric pathology of infection tends to progress from mild symptoms, via active gastritis, atrophy, gastric intestinal metaplasia (GIM) and dysplasia towards gastric adenocarcinoma. Intriguingly, GIM is usually cleared of Hp, suggesting this pathological state is not merely an intermediate stage towards cancer development, but can be viewed as a process of adaptive defence.
Mutations in the tumor suppressor gene TP53 are frequent events of epithelial malignancy in numerous tissues. Based on compelling evidence from an analysis of congenic mutant organoids and related observations, I pursue the hypothesis that pre-malignant mutations in the epithelium arise as an adaptive response to persistent infections and thus constitute a novel layer of antimicrobial defence and tissue protection. MADMICs will have its main focus on the mutational and epigenetic changes associated with GIM and also touch comparable mucosal pathologies investigated by the PI in recent years. An apparent hallmark of such persistent bacterial infections and related cancers is their link to the function of tumor suppressor p53.
MADMICs will capitalize on the PI’s profound experience with pathogens, primary cell culture and chronic infection models. Organoids from normal and premalignant human tissues and isogenic mutant organoids created via CRISPR/Cas9 will be used to explore host cell signaling and mutator pathways with regard to early cancer mutations and their antimicrobial effects. The study will illuminate an unprecedented mechanism of microbial defence from a number of perspectives and likely lead to a paradigm shift of our view on the link between adaptive host responses and early cancer mutations.

Meccanismo di finanziamento

ERC-ADG - Advanced Grant

Istituzione ospitante

CHRISTIAN-ALBRECHTS-UNIVERSITAET ZU KIEL
Contribution nette de l'UE
€ 2 500 000,00
Indirizzo
OLSHAUSENSTRASSE 40
24118 Kiel
Germania

Mostra sulla mappa

Regione
Schleswig-Holstein Schleswig-Holstein Kiel, Kreisfreie Stadt
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 2 500 000,00

Beneficiari (1)