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

Projektbeschreibung

Immunmechanismen der therapeutischen Resistenz bei Morbus Crohn

Morbus Crohn ist eine chronisch entzündliche Erkrankung des Magen-Darm-Trakts, von der weltweit Millionen von Menschen betroffen sind und die eine erhebliche körperliche, emotionale und wirtschaftliche Belastung darstellt. Die derzeitigen Therapien, wie etwa die TNF-Hemmung, zielen darauf ab, die Entzündung zu unterdrücken, doch viele Patientinnen und Patienten sprechen nicht darauf an. Das EU-finanzierte Projekt CD-ResOMics wird untersuchen, welchen Anteil die Immunregulation am Scheitern der Primärtherapie hat. Die Forscherinnen und Forscher werden die Genexpressionsprofile einzelner Zellen aus Darmbiopsien der auf die Behandlung ansprechenden und nicht darauf ansprechenden Patientenschaft im Laufe der Zeit analysieren. Anhand von gepaarten Blutproben werden potenzielle Biomarker für die Stratifizierung der Patientenschaft ermittelt. Die Studie wird die zellulären und molekularen Grundlagen der Resistenz aufdecken und zu verbesserten therapeutischen Strategien für Morbus Crohn führen.

Ziel

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.