Scholarship 24/02645-3 - Neoplasias bucais, Esfingolipídios - BV FAPESP
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Extracellular vesicles, sphingolipids and factors derived from oral epidermoid and tumor cells in differentiating macrophages into M1 and M2 subtypes

Grant number: 24/02645-3
Support Opportunities:Scholarships in Brazil - Master
Start date until: August 01, 2024
End date until: June 30, 2025
Field of knowledge:Health Sciences - Dentistry
Principal Investigator:Andréia Machado Leopoldino
Grantee:Guilherme da Silva Carvalho
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:16/19103-2 - SET and sphingolipids in head and neck squamous cell carcinoma: signaling, targets and antiumoral therapy, AP.TEM

Abstract

Intercellular communication is a key point in the polarization of macrophages towards the M1 and M2 subtypes. The M1 subtype has a pro-inflammatory profile while the M2 does not. Among the various changes that occur in cells and in the tumor microenvironment, we highlight the deregulation of sphingolipids. Recently, our group showed that the increase of sphingosine kinase 2 (SPHK2) in non-tumor oral keratinocytes (NOK) induced the cell's transformation to a mesenchymal and tumorigenic phenotype. In parallel, we showed that the increase in SPHK1 did not have the same action. Considering that little is known about the relationship between SPHK2 and SPHK1 with macrophage polarization for M1/M2 subtypes and that M2 is related to cancer, our hypothesis is that macrophage differentiation in the tumor microenvironment is regulated by SPHK2, which favors the escape of the tumor immune response. Therefore, the objective is to characterize whether oral epidermoid cells with increased levels of SPHK2 and SPHK1 have an action on the polarization of macrophages to M1 or M2 and whether the mechanism involves extracellular vesicles (EV). Human oral epidermoid cell lines with altered levels of SPHK1 and SPHK2, THP-1 cells and monocytes isolated from peripheral blood of healthy donors will be used. Molecular markers of macrophage subtypes M1 and M2 will be analyzed by real-time PCR, immunofluorescence, confocal microscopy and flow cytometry. The VE profile will be determined by analyzing the size and number of nanoparticles and exosome fractions will be obtained by ultracentrifugation. The expected results will clarify and expand our understanding of the role of sphingosine kinases, sphingolipids and VE in the polarization of M1/M2 macrophages in oral squamous epithelium, contributing to knowledge of the pathophysiology of oral cancer and, potentially, other oral diseases.

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