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Regulation of the Th17/Treg axis by HIF-1a in experimental type 1 diabetes susceptibility

Grant number: 22/13074-1
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): December 01, 2022
Effective date (End): November 30, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Niels Olsen Saraiva Câmara
Grantee:Natalia Notarberardino Bos
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology, AP.TEM


Type 1 Diabetes Mellitus is an autoimmune disease in which pancreatic ² cells are destroyed by T cells CD8+ and CD4+ that recognize self-antigens. This disease has an alarming raise of cases in the last couple of years. ² cells are responsible for insulin production. That said, loss of ² cells result in hyperglycemia with effects in the nervous system and even death. It has been reported in autoimmune diseases some level of unbalance between pro-inflammatory T cells and Tregs, resulting in loss of immune homeostasis, meaning a poor prognosis. With that in mind, the understating of mechanisms responsible for T cell differentiation is primordial to understanding the progression of type 1 diabetes. The transcription factor HIF-1± is responsible for the metabolic switch through hypoxic conditions, increasing glycolysis. Furthermore, HIF-1± up-regulates ROR"³" t and IL-17 transcription while stamps FOXP3 for degradation. Therefore, HIF-1± foments Th17 instead of Treg differentiation, resulting in a pro-inflammatory T cell. That said, this project aims the better understanding of how this factor can decrease the susceptibility to diabetes. This is going to be achieved by inducing diabetes with multiple injections of streptozotocin in C57BL/6 RORCcreHIF-1a flox/flox and WT mice. Spleen and pancreatic lymph node will be to investigate the differentiation profile of T cells in the absence of HIF-1 ±. Finally, we expect the disease's response to be more regulatory, resulting in less loss of ² cells by T cells CD4+.

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