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Evaluation of the activation and role of the NLRP1 inflammasome in the immune response in type 1 diabetes

Grant number: 16/10641-1
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2016
Effective date (End): March 31, 2018
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Daniela Carlos Sartori
Grantee:Frederico Ribeiro Campos Costa
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:12/10395-0 - Role of NLRs receptors in immunoregulation mechanisms of the type 1 and 2 diabetes: identification of potential therapeutic targets, AP.JP


Type 1 diabetes (T1D) is an autoimmune disease that is determined by both genetic and environmental factors. The disease is characterized by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells, leading to a state of hyperglycemia. In this context, Th1 and CD8+ play an important role in the autoimmune response, whereas regulatory T(reg) cells participate in the control of the disease. Besides, studies conducted by our group show that the increase in Th17 cells correlates with T1D progression, and that the deficiency for IL-17R inhibits the tissue-specific pancreatic inflammation.There is increasing evidence showing that cytokines such as IL-1beta, IL-6, TGF-beta, IL-18 e IL-23 participate in the differentiation/expansion of Th17 cells, being secreted in their biologic active state, with the exception of IL-1beta and IL-18. These cytokines become activated only after the proteolytic cleavage by caspase-1 during the formation of a complex called the inflammasome. This complex consists of a molecular platform in which members of the cytosolic receptors family participate, including NLRP1, NLRP3, NLRP6 and NLRC4. Even though there are studies confirming polymorphisms in the Nlrp1 gene in diabetic patients, the precise role of the activation and function of this receptor during T1D remains elusive.Therefore, we aim to investigate the intracellular mechanisms involved in the activation and role of the NLRP1 inflammasome in the regulation of a Th1/Th17 pathogenic immune response using experimental models of T1D (induced by streptozotocin and nonobese diabetic mice). In parallel, we will investigate the possible role of this receptor in the stability/plasticity of Treg cells by analyzing epigenetic alterations. With this project, we intend to identify new possible molecular targets that might become a new therapy in the future for diabetic patients.

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
COSTA, Frederico Ribeiro Campos. The NLRP1 receptor acts as a regulator of the Th17 response profile in Experimental and human models with type 1 diabetes. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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