Elucidating the cellular basis of therapeutic resistance in Crohn's disease

Descrizione del progetto

Meccanismi immunitari di resistenza terapeutica nel morbo di Crohn

Il morbo di Crohn è una patologia infiammatoria cronica del tratto gastrointestinale che colpisce milioni di persone in tutto il mondo e che comporta un notevole carico fisico, emotivo ed economico. Le terapie attuali, come il blocco del TNF, mirano a sopprimere l’infiammazione, ma molti pazienti non rispondono. Il progetto CD-ResOMics, finanziato dall’UE, studierà come la regolazione immunitaria contribuisca al fallimento della terapia primaria. I ricercatori analizzeranno i profili di espressione genica di singole cellule provenienti da biopsie intestinali di soggetti che rispondono e non rispondono al trattamento nel corso del tempo. I campioni di sangue accoppiati identificheranno potenziali biomarcatori per la stratificazione dei pazienti. Lo studio rivelerà le basi cellulari e molecolari della resistenza, guidando il miglioramento delle strategie terapeutiche per il morbo di Crohn.

Obiettivo

Crohn´s Disease (CD) is a chronic inflammatory disease that affects the gastrointestinal tract, affecting millions of people worldwide and presenting a considerable economic burden to health systems. CD has a serious impact in quality of life, not just physically, but also emotionally and socially. Pathogenesis results from a complex interaction between environmental factors, microbiome, genome, and inflammatory system, leading to disruption of the intestinal mucosa. The imbalance between inflammatory and regulatory cells in maintaining an active disease is well known, and most therapies aim to stop the cascade of inflammatory and pro-inflammatory cytokines (i.e. TNF-blockade). One of the major challenges for treatment is the fact that not all patients respond to therapy. Moreover, the mechanisms behind resistance are still not completely understood, making it hard to correctly stratify patients as responders and non-responders at time of diagnosis. We aim to elucidate changes in immune regulation that explain primary response failure to TNF-blockade in CD. We hypothesise that dysfunction of regulatory cells may prevent reinstatement of homeostasis following inflammation targeting. We will establish single-cell transcriptomics of immune cells from biopsies at the time of diagnosis, as well as in patients responding to treatment and non-responders. Then, we will use computational methods to investigate how immune cells change with time, acquiring a state supporting therapeutic resistance. Moreover, we will illuminate the relationship between immune dysregulation and anatomic niches using spatial transcriptomics. Finally, we will analyse paired peripheral blood samples, for the identification of putative biomarkers for stratification of patients according to TNF-blockade response.
This proposal will provide unprecedented insights on the mechanisms involved in therapeutic resistance in CD, which could potentially lead to the development of new treatment approaches.