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

Descripción del proyecto

Mecanismos inmunitarios de resistencia terapéutica en la enfermedad de Crohn

La enfermedad de Crohn es un trastorno inflamatorio crónico del tracto gastrointestinal que afecta a millones de personas en todo el mundo y supone una importante carga física, emocional y económica. Los tratamientos actuales, como el bloqueo del factor de necrosis tumoral (FNT), pretenden suprimir la inflamación, pero muchos pacientes no responden. El equipo del proyecto CD-ResOMics, financiado con fondos europeos, investigará cómo contribuye la regulación inmunitaria al fracaso del tratamiento principal. Los investigadores analizarán los perfiles de expresión génica de células individuales procedentes de biopsias intestinales de pacientes que responden o no al tratamiento a lo largo del tiempo. Las muestras de sangre emparejadas identificarán biomarcadores potenciales para la estratificación de los pacientes. El estudio revelará las bases celulares y moleculares de la resistencia, lo que permitirá mejorar las estrategias terapéuticas para la enfermedad de Crohn.

Objetivo

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.