| Grant number: | 19/23469-0 |
| Support Opportunities: | Scholarships in Brazil - Master |
| Start date: | February 01, 2020 |
| End date: | January 31, 2022 |
| Field of knowledge: | Biological Sciences - Immunology - Cellular Immunology |
| Principal Investigator: | Sandro Félix Perazzio |
| Grantee: | André Luiz Soares da Cunha |
| Host Institution: | Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil |
| Associated research grant: | 18/00555-6 - NF-kB pathway hyperactivation and its interplay with CD40L on Behçet's Disease: a possible link for the autoinflammatory phenotype, AP.JP |
Abstract Behçet's disease (BD) is currently classified as a polygenic autoinflammatory syndrome. Recently point mutations in NFKB1, TNFAIP3 and NEMO were associated with BD-like phenotypes, showing the importance of the NF-kB pathway on BD pathogenesis. Constitutional or acquired trisomy 8, which encodes IKBKB, an important NF-kB activator, is often associated with BD. In addition, sCD40L, which, in turn, has as abnormal plasma concentration in BD, can stimulateoxidative burst via PI3K/NF-kB. However, the influence of the above-mentioned mutations inimmune cells and sCD40L-mediated signaling remain unclear.Purpose: 1) analyze the functional behavior of HL-60, THP-1, Daudi, Jurkat and U293F cell lines influenced by NF-kB pathway components hyperexpression and mutations, focusing on sCD40Linduced activation; 2) create a BD-like mouse model by injecting high doses of sCD40L. Methods: 1) In vitro study: lentiviruses labeled with green fluorescent protein carrying NFKB1,NFKB2, NEMO, TNFAIP3 and IKBKB and their respective mutant variants R157X, R853X, D406V and L227X will transduce the cell lines. The hyperexpression of the NF-kB pathways wild type and mutant genes transduced will be confirmed by flow cytometry. Cell lines will be assessed regarding: neutrophil extracellular traps release; oxidative burst; phagocytic; in vitro production of TNFa, IL1b e IL-6; genetic and protein expression of NF-kB pathway components and target genes. 2) Experimental study: CD40L-deficient and C57BL/6J mice will receive weekly intraperitoneal injections of sCD40L for 90 days. Plasma levels of sCD40L will be determined every other week by ELISA. After this period, the animals will be sacrificed for a comprehensive histopathological study and exsanguinated for quantification of serum autoantibodies. (AU) | |
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