Targeting the Galectin-glycan interactions in Inflammatory Bowel Diseases

MARIÑO, KARINA V.; RABINOVICH, GABRIEL A.

Los Angeles

Congreso; Grantee Meeting, Broad Medical Research Program, Crohn and Colitis Foundation of America; 2014

Broad Foundation

In the postgenomic era, the study of the glycome (the whole repertoire of glycans in cells and tissues) has enabled the association of unique N- and O-glycan structures with specific physiologic and pathologic processes. The responsibility for deciphering this information belongs to endogenous glycan-binding proteins including C-type lectins, siglecs and galectins.I In previous studies, we have identified essential roles for galectin-1 (Gal-1) a highly- conserved β-galactoside-binding lectin in the control of intestinal inflammation through regulation of the mucosal immune system. II Recently, we found that Gal-1 acts a selective immunosuppressive agent by preferentially deleting pathogenic Th1 and Th17 cells, by instructing the differentiation of tolerogenic dendritic cells (DCs) and/or by promoting the generation of alternatively-activated ?M2-type? macrophages.III-VWith the ultimate goal of implementing novel therapeutic approaches in IBD, in this project we aim to investigate how interactions between Gal-1 and its specific glycans, generated during the transition from normal to inflamed tissue, can mediate cellular processes relevant to immune tolerance and inflammation in IBD. We will study changes occurring in the cell surface ?glycome? during the transition from healthy to inflamed mucosa in murine experimental models of colitis and in biopsies from Crohn?s disease and ulcerative colitis patients, focusing on the study of Gal-1 and the ?Gal-1-associated glycome? (glyco-epitopes that are specific for Gal-1). This work will be carried out using samples of a selected cohort of IBD (Crohn?s disease and ulcerative colitis) patients, including mucosal tissue and purified CD4+ T cells, as well as complementary experimental murine models of colitis. Furthermore, we will assess the immunomodulatory and anti-inflammatory activity of Gal-1, and of genetically-engineered bacteria expressing Gal-1. Understanding the relevance of Gal-1 and its interactions with specific glycans (?Gal-1-linked glycome?) will contribute to a better understanding of the immunopathologic mechanisms underlying intestinal inflammation and to the development of novel therapeutic strategies in IBD patients.