Identification of cell interactions that affect regulatory T cells function in inflammatory bowel diseases

• Grant number: 23/17817-1
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2025
• End date: January 31, 2030
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Raphael Sanches Peres
• Grantee: Raphael Sanches Peres
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Luiz Gustavo Araujo Gardinassi ; Rogerio Serafim Parra ; Sandro da Costa Ferreira
• Associated research grant(s): 25/04210-7 - Multi-user equipment approved in grant 2023/17817-1: CytAssist (10x Genomics), AP.EMU; 25/04216-5 - Multi-user equipment approved in grant 2023/17817-1: microscope Leica DMi8, AP.EMU
• Associated scholarship(s): 25/02121-7 - Characterization of immune system cells from the peripheral blood of patients with Crohn's disease, BP.TT; 25/02602-5 - Spatial and functional characterization of intestinal cells from patients with Crohn's disease, BP.TT; 25/00038-5 - IDENTIFICATION OF CELL INTERACTIONS THAT AFFECT REGULATORY T CELLS FUNCTION IN INFLAMMATORY BOWEL DISEASES, BP.JP; 25/00092-0 - Visualization of cell interactions between Tregs and other cell types in the intestine from patients with Crohn's disease, BP.IC

Abstract

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders that affects the gastrointestinal tract (GI), including Crohn's disease (CD) and ulcerative colitis (UC). Although its etiology is unknown, a dysbalance of the immunity against to intestinal microbiota associated with genetic and environmental factors are seemed to contribute to IBD pathogenesis. Due to a lack of understanding of the molecular and cellular mechanisms involved with IBD pathogenesis, its treatment is challenging. Recent studies analyzing intestinal cell populations at the single-cell level have provided relevant information related to IBD pathophysiology as well as events associated with response to therapy. Despite these advances, studies are still limited in resolution to characterize cell populations found in low numbers/frequencies in tissue and circulation. Furthermore, the techniques approached in these studies, such as single cell RNA sequencing (scRNA-seq), do not allow determining tissue spatial organization and how interactions occur among different cell types in the intestine. For example, although regulatory T (Treg) cells are described as critical components for the maintenance of tolerogenic responses and associated with IBD development, the heterogeneity of Tregs is not fully characterized and little is understood about which interactions of Tregs with other cell types contribute to tissue homeostasis and disease. Within this context, this project proposes: i) create a database for hypotheses generation using spatial transcriptomics in intestinal samples from patients with CD and healthy individuals; ii) define interactions that occur between Tregs and other cell types in the intestine from patients with CD and experimental model of colitis; iii) perform in vitro functional assays using co-culture of cells isolated from the intestine and 3D-organoids to determine which interactions affect Treg function; iv) explore the therapeutic relevance of the identified targets using experimental models of intestinal inflammation. In this way, this proposal will provide novel relevant insights about IBD pathogenesis, especially for CD, which may be useful to develop strategies for therapeutic intervention and identification of biomarkers and/or events associated with response to therapy. (AU)