Scientific Abstract
Proposal No. IBD-0186R
Principal Investigator: Andreas Sturm, M.D.
Applicant Organization: Charité - Universitätsmedizin Berlin (Germany)
Project Title: Galectin-2: Evaluation of a novel anti-inflammatory approach in the treatment of inflammatory bowel disease
Period of Award: January 1, 2007 – December 31, 2008
Galectins, a growing family of animal lectins, has recently attracted the interest of cell biologists and immunologists as master regulators of immune cell homeostasis. Galectins are present both inside and outside cells, and the expression of galectins is modulated during the activation and differentiation of immune cells. Some of the extracellular functions reported for galectins include cell-growth regulation, apoptosis, activation, cell adhesion, and chemotaxis. Galectins are distributed in a wide variety of tissues, but galectin-2 is of special interest to IBD since its expression is restricted to the gastrointestinal tract.
Until recently the biological function of galectin-2 was unknown, but lately we demonstrated that this lectin potently induces apoptosis of activated, but not resting T cells, down-regulates pro-inflammatory cytokine secretion, and blocks adhesion of activated T cells to the extracellular matrix, all being effects beneficial for the treatment of IBD. Furthermore, preliminary experiments demonstrated that in IBD tissue intracellular galectin-2 expression levels are decreased, maybe contributing to the impaired T cell apoptosis observed in this condition.
Therefore, we hypothesize that galectin-2 is involved in the pathogenesis of IBD and may have a potential therapeutic effect in intestinal inflammation. We aim to answer this question by studying galectin-2 expression in the intestine of IBD patients before and after treatment. By employing proteomic analysis to examine immune abnormalities, we hope to identify different therapeutic modalities and predict patient responses. Identification of unique subsets of patients may facilitate the transfer of knowledge gained at the bench to the bedside and conversely, rapid transfer of clinical findings to advance work at the bench. Furthermore, by investigating the effect of galectin-2 on T cell function in control and IBD patients as well as in models of experimental colitis we aim at unraveling the mechanisms of its regulation and its potential therapeutic effects.
The herein proposed studies will complement and strengthen the mounting body of evidence that galectins are key regulators of the immune system which modulate a wide range of different inflammatory pathways. Considering that the treatment of IBD is still a major challenge, and that the heterogeneity of the patient response to therapy is likely due the heterogeneity of mechanisms of inflammation, the significance of our proposal is further reinforced by the possibility that manipulation of the galectin pathway can offer a new tool in the therapeutic arsenal against IBD.