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Uncovering the role of mTORC1-regulated metabolic enzymes in systemic lupus erythematosus

Grant number: 19/08367-7
Support type:Scholarships abroad - Research
Effective date (Start): June 21, 2019
Effective date (End): March 20, 2020
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Alexandra Ivo de Medeiros
Grantee:Alexandra Ivo de Medeiros
Host: Jeffrey C Rathmell
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Local de pesquisa : Vanderbilt University (VU), United States  

Abstract

The pathogenesis of Systemic lupus erythematosus (SLE) is coordinated by autoantibody production against nuclear and phospholipid antigens that play an essential role in tissue damage. However, CD4+ T cell activation has been recognized as a critical player in SLE pathogenesis. Many reports have shown that patients with SLE have an increased frequency of CD4+IL-17+ T cells, as well as high serum levels of IL-6, IL-23, and IL-17. The mTOR pathway plays an essential role in CD4+ T cell differentiation, and patients as well as experimental models for SLE, mTORC1 is activated in CD4+ T lymphocytes. A recent clinical trial demonstrated that the treatment with mTOR inhibitor (sirolimus) in patients unresponsive to conventional drugs has improved the disease symptoms, promoted the expansion of CD4+CD25+FoxP3+ regulatory T cells as well as the inhibition IL-17 and IL-4 production. Even though rapamycin appears to be an effective short-term treatment in SLE patients, the mTORC blockage may compromise anabolic cell functions in long term usage. Increasing efforts have been made to elucidate metabolic disorders in the context of autoimmune diseases and, consequently, discover potential therapeutic targets. Our objective in this study is to investigate whether the inhibition or deletion of mTORC1-regulated genes encoding enzymes from glycolysis, the pentose phosphate pathway (PPP) and lipid/sterol biosynthesis could inhibit the Th17 differentiation in human and in lupus-prone mice. Also, the expression of those mTORC1-regulated genes encoding the metabolic enzymes will be determined in T cells from patients with active (A-SLE) or inactive SLE group (I-SLE) to correlate with disease severity or progression, representing a potential biomarker.