The role of the TRPM5 receptor in the activation and differentiation of CD4+ T cells and its relevance in an experimental model of intestinal inflammation

• Grant number: 22/14364-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2024
• End date: February 28, 2027
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: João Vinícius Honório da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/07482-2 - Sensing extra and intracellular stressors by renal and immune cells: new insights into signal reception and transduction, and their relevance for understanding renal diseases, AP.TEM
• Associated scholarship(s): 25/11561-0 - Dissecting the role of TRPM5 in ¿¿T (gamma-delta) cell function at the gut-brain axis interface, BE.EP.DR

Abstract

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disorder of the gastrointestinal tract, with an increased incidence in several countries, including Brazil. Intestinal inflammation is developed with the help of different types of leukocytes, including CD4+ T cells, especially the subsets of Th17 and T regulatory cells, which are intimately involved in the pathogenesis of IBD, and can play both a protective role, balancing the microenvironment. immunological, as a pro-inflammatory role. It is known that the activation and differentiation of CD4+ T cells is calcium (Ca2+) dependent. Since TRPM5, an ion channel mainly involved in taste transduction, controls the intracellular Ca2+ concentration, we believe that it can influence the polarization of CD4+ T cells. Therefore, our hypothesis is that TRPM5 knockout (KO) animals would be protected from intestinal inflammation, due to alteration in CD4+ T cell activation and differentiation, suppressing the inflammatory response. For this, we will seek to investigate the influence of TRPM5 on the activation and differentiation of CD4+ T cells in the intestinal mucosa, using experimental strategies such as: 1) C57BL/6 wild-type (WT) and TRPM5 KO mice; 2) In vivo assays - TRPM5 channel expression profile in naïve, Th0, Th1, Th2, Th17 and Treg CD4+ T cells; 3) In vivo assays - TRPM5 in DSS-induced intestinal inflammation; 4) In vitro assays - mechanisms involved in the activation and differentiation of CD4+ T cells; 5) In silico analysis - RNAseq. The results obtained in this project may contribute to the understanding of the mechanism of action of TRPM5 on CD4+ T lymphocytes and in the pathogenesis of IBD, in addition to opening perspectives for future therapeutic interventions to control inflammatory processes.