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Influence of the genetic background on PLSCR1 tyrosine phosphorylation in IgE receptor-activated mast cells

Grant number: 19/26194-2
Support type:Scholarships abroad - Research Internship - Scientific Initiation
Effective date (Start): July 31, 2020
Effective date (End): September 29, 2020
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal researcher:Mariane Tami Amano
Grantee:Elayne Bragança Jardim
Supervisor abroad: Marc Benhamou
Home Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
Research place: Université Paris Diderot - Paris 7, France  
Associated to the scholarship:18/20815-2 - The effect of the combined treatment of BET inhibitors and signaling pathways on the induction of DNA damage in leukemic cells, BP.IC

Abstract

Mast cells play important roles in allergic reactions, in detoxification, in immune defence against infection and in the regulation of adaptive immunity. When activated, their polarized degranulation ensures that the enzymes remain concentrated witch optimizes the target neutralization. Also, vasoactive amines contained in the same granules release by them can favour recruitment of other immune cells from the bloodstream. They present antigen to lymphocytes thus participating in the triggering of the immune response as well as participate in the resolution phase of inflammation through the production of extracellular matrix proteins. All these roles of mast cells are possible because of the vast array of mediators that they produce as well as the large number of receptors that they express, like Fc receptors such as IgE (FceRI). In particular, the FceRI is interesting since the IgE system is central in allergic reactions and in the defence against parasitic infection. In the literature, the FceRI signalling pathway was shown to involve tyrosine phosphorylation. In this way, the phospholipid scramblase 1 (PLSCR1) was identify as an important intermediate signal and regulator of FceRI signalling. More importantly, PLSCR1 appeared as an amplifier of FceRI-dependent mast cell degranulation without impacting the production of arachidonic acid metabolites or cytokines, which could be used for future selective intervention to stimulate or block mast cell degranulation without affecting other functions of these cells. Therefore, the objective of this project is to compare the level of expression and the phosphorylation status in the regulation of PLSCR1 in mast cells of different genetic mice backgrounds to understand how genetic backgrounds could affect PLSCR1 regulation. For this, we will first generate bone marrow-derived mast cells (BMMC). Then, the mast cells will be stimulated and the measurement of the cell degranulation will be performed. After that, the cells will be lysated to PLSCR1 immunoprecipitation assay and immunoblotting analysis. In this way, we intent to investigate if the function of PLSCR1 would depend on the genetic background, since it acts between the Lyn- and Fyn-initiated pathways (Lyn and Fyn phosphorylate the e g and b chains of FceRI) and it belongs to the Lyn-initiated pathway that it selectively modulated. More specifically, we expect that although PLSCR1 plays an amplifier function in FceRI-mediated mast cell degranulation in a C57Bl/6J mice background, it would play a dampener role of FceRI-mediated degranulation in 129/Sv mice background, thus following the general function of the Lyn-initiated pathway. (AU)

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