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Annexin A1 pathways triggered in the inflammatory bowel disease treated with Infliximab

Grant number: 16/19682-2
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2016
Status:Discontinued
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Sandra Helena Poliselli Farsky
Grantee:Marina de Paula Silva
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:14/07328-4 - Identification of endogenous pathways for the control of inflammation, AP.TEM
Associated scholarship(s):19/02806-9 - Involvement of formyl-peptide receptor pathways and ligands in the efficacy of Infliximab therapy, BE.EP.DR

Abstract

Inflammatory bowel diseases (IBDs) are characterized by severe inflammation in the gastrointestinal tract. The TNF-alpha exerts a benefitial role against infections during IBDs, but the dysregulation of this cytokine constitutes a key factor to the triggering and maintenance of intestinal inflammation. Therefore, TNF-alpha neutralizing tools, such as the anti-TNF-alpha antibody Infliximab (IFX) have been applied to induce remission of IBDs in conventional therapies refractory patients. Studies have shown that IFX regulates the endogenous expression of the anti-inflammatory protein annexin A1 (AnxA1). Besides, our research group recently demonstrated that AnxA1 participates of the IFX treatment efficacy. However, the mechanisms involved in the endogenous AnxA1 modulation and remission of IBDs after IFX remain unclear. Adverse events non-responsiveness after IFX are still reported, bringing the need to investigate the pathways through TNF-a, AnxA1 and IFX interact. Thus, our aim is assess the mechanisms of endogenous AnxA1 in the pathogenesis of IBDs and in IFX therapy efficacy, focused in the cells involved in these processes. First, we are going to investigate whether the AnxA1 acts via FPR and, still, the therapeutic effect of an AnxA1 mimetic peptide. DSS colitis model will be induced in WT and AnxA1-/- mice, which will be treated with either the pan FPR receptor antagonist, Boc-2, or the AnxA1 N-terminal peptide, Ac2-26, respectively. Both Boc-2 and Ac2-26 will be administered simultaneously with IFX to evaluate the relationship of the AnxA1 with this therapy. To highlight the pathways through AnxA1 is related to IBDs pathogenesis and IFX treatment, we will perform in vitro assays with epithelial cells (Caco-2), macrophages and dendritic cells derivated from human monocytes (U937), manipulated or not to the silencing of endogenous AnxA1. Finally, tridimensional culture with the same cell types above, positive or negative to AnxA1, will mimic the relationship between the main cells involved in the IBDs. We believe that the results obtained from the proposed experiments will contribute to the better understanding of the IBDs pathogenesis and the mechanisms involved in the efficacy of the anti-TNF-alpha treatment, providing important subsides to improve the existent therapies and, consequently, the life quality of the patients.