The role of sirtuin 1 in the phenotype and function of dendritic cells in the context of organ transplantation in obese animals

• Grant number: 18/04326-1
• Support Opportunities: Scholarships in Brazil - Master
• Start date until: June 01, 2018
• End date until: January 31, 2021
• Field of knowledge: Biological Sciences - Immunology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Jean de Lima
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 19/07820-0 - Sirtuins functions in lineages of conventional dendritic cells and IL-35 producing dendritic cell constitutively, BE.EP.MS

Abstract

Advances in surgical procedures, compatibility tests and development of immunosuppressive drugs have helped to increase allograft survival. However, acute rejection and chronic graft dysfunctions still remain as barriers to be overcome. In addition, obesity has emerged as a new risk factor for rejection and graft dysfunction via several immunological effector mechanisms. Sirtuin 1 (Sirt1) belongs to class 3 histone deacetylases (HDACs) and acts primarily by regulating the differentiation, proliferation and activation of T cells. This HDAC can act by deacetylating and, consequently, by deactivating dendritic cell (CD) gene transcriptions that are important for activation and differentiation of T cells, namely effector cells in graft rejection. Therefore, our hypothesis is that obesity influences the differential expression of sirtuins in CD altering its phenotype and function and with that the activation of T cells, exacerbating the allograft immune response. Thus, our objective is to investigate the role of Sirt1 in CD function and phenotype and its implications on their cellular metabolism and in the differentiation/function of T cell subtypes in the context of the skin allograft of obese animals. This way, the impact of Sirt1 on skin allografts rejection or acceptance will be studied in animals in which it will be specifically excluded in CD (Sirt1”CD11c) and in control (CT; SIRT1 + / + - CD11c -Cre). Cytokine levels, expression of transcription factors and clusters of differentiation, as well as capacity, allostimulation and induction of T cell subtypes by the use of flow cytometry, western blot, ELISA, RT-PCR and functional assays. The metabolic activity of the CD will be studied by methods of fluorescence, gene expression and molecules of various metabolic pathways and by Seahorse (real-time metabolic analysis). In the transplanted animals, the role of Sirt1 in CD will be studied by the evolution of the transplant, analysis and function of the T cells and profile of the CD in the draining lymph nodes. We sought to fill in the gaps in the knowledge about the mechanisms of action of Sirt1 in the allografts acceptance and rejection and in the metabolic control of the key antigen presenting cells in these processes. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

LIMA, Jean de. Sirtuin 1 (SIRT1) belongs to class 3 histone deacetylase (HDAC3) with a role in differentiating and activating dendritic cells (DCs). 2021. Master's Dissertation - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.