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Targeting cellular antioxidant system to sensitize Glioma Stem Cells to radiation-induced oxidative damage

Grant number: 16/16163-4
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): November 01, 2016
Effective date (End): October 31, 2017
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Elza Tiemi Sakamoto Hojo
Grantee:Paulo Roberto D'Auria Vieira de Godoy
Supervisor abroad: Siamak Haghdoost
Home Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Stockholm University, Sweden  
Associated to the scholarship:13/13253-4 - Cellular and molecular responses of irradiated glioblastoma cell lines under inhibition of E2F transcription factors family members, BP.PD

Abstract

Glioblastoma (GBM) is a malignant brain tumor with poor outcome and is very resistant to treatment. Glioma stem cell (GSC) presents an enhanced antioxidant defense compared to their serum-differentiated counterparts and is resistant to chemo- and radio- therapy. We propose to analyze some of the most important antioxidant proteins/expressed genes (e.g. gluthathione, glutathione peroxidase, glutathione redutase, catalase, peroxiredoxin, superoxide dismutase, etc) in undifferentiated and differentiated GSC exposed to chronic and acute doses of ionizing radiation, by using Western Blot, RT qPCR and ELISA. The proteins that will show high expression levels in undifferentiated GSCs will be used as targets to boost the radiation effects. This will be achieved by means of shRNA specific for the antioxidant enzyme, or other proteins necessary for non-enzymatic antioxidant biosynthesis. Several analyses will be performed, such as ROS generation (DHE and Mitosox detection), oxidative stress (8-oxo-dg detection), cell differentiation (stemness and differentiation markers), and self-renewal (sphere formation assay), in irradiated or sham-irradiated silenced GSCs. Our hypothesis is that reducing the antioxidant capacity of GSCs and increasing ROS production by chronic and acute low dose irradiation will reduce GSCs functionality by increasing differentiation and decreasing self-renewal. To achieve these results, experiments will be carried out in the laboratory of Dr. Siamak Haghdoost, at Stockholm University, which presents all facilities to perform the techniques required for this project. We expect that the present study will provide interesting results regarding glioma radiosensitization, and they may be used for designing alternative therapies for patients with GBM, with a new approach based on decreased anti-oxidant defense combined to radiotherapy.