|Salome de Pinho © ECCO|
The current therapeutic strategies for Inflammatory Bowel Disease (IBD) are limited by effectiveness and/or toxicity, and the selection of patients for therapy remains a major challenge. These clinical concerns highlight the unmet need to identify key mechanisms (molecular markers) capable of being selectively targeted with new and optimised therapies. Glycosylation is a major post-translational mechanism characterised by the addition of carbohydrate structures (glycans) to essentially all cells . Evidence in other immune-mediated disorders has shown that protein N-glycosylation, particularly branched N-glycans, regulates T cell immune response and controls the threshold of T cell activation .
Recently, we found that Ulcerative Colitis patients exhibit a deficiency in branched glycosylation in intestinal T cells that is reflective of disease severity . The main goal of this project is to assess whether glycosylation of T cells is a previously uncovered factor that tips the balance between homeostasis and intestinal inflammation, and whether it represents a mechanism that could be specifically targeted, stimulating the development of new IBD therapies.
Our team will accomplish this goal through completion of specific tasks that will combine state-of-the-art technology applied to ex vivo models (T cells purified from a well-characterised cohort of IBD patients) and different IBD in vivo models. We will test the impact of specific glycans as immunomodulatory agents both ex vivo and in preclinical mouse models of IBD.
1. Dias AM, Almeida CR, Reis CA, Pinho SS. Studying T cells N-glycosylation by imaging flow cytometry. Methods Mol Biol. 2016; 1389:167–76.
2. Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer. 2015;15:540–55.
3. Dias AM, Dourado J, Lago P, et al. Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis. Hum Mol Genet. 2014;23:2416–27.