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Analysis of the role of NRF2-coordinated autophagy and its impact on the chemotherapy response in glioblastoma cells.

Grant number: 23/02349-2
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): August 01, 2023
Effective date (End): February 28, 2025
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Mariana Lazarini
Grantee:Ana Beatriz da Silva Teixeira
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg), AP.TEM
Associated scholarship(s):23/18067-6 - The Role of Autophagy pathways in Ferroptosis in tumor cells, BE.EP.MS

Abstract

Glioblastoma represents a devastating diagnosis for the patient, considering that, without treatment, its average survival is only 4 months. This time is increased to 12 months after physiological resection followed by radiotherapy, with the combination of temozolomide (TMZ), standard chemotherapy, adding only another 3 months to this period. Precisely the frequent development of resistance to TMZ is one of the greatest obstacles to prolonging the survival of patients with glioblastoma. And for cancer cells to be able to resist chemotherapy, one of the controls most commonly used by them is autophagy, which is a highly conserved evolutionary process of protection against stressors. Thus, autophagy may have a positive perspective when seeking a modulation of this process as a complementary tool for already protected improved therapies. Interestingly, the silencing of NRF2, a transcription factor capable of inducing autophagy, allowed the sensitization of glioblastoma cells to TMZ. However, the studies already carried out are limited to investigating the relationship of NRF2 with chaperone-mediated autophagy (CMA) and macroautophagy (MA) in an automated way, even though a robust explanation of the activity of MA in deficient cells has already been verified. in CMA and vice versa. Therefore, it is still necessary to understand the importance of this functional crosstalk between these two types of autophagy and its coordination by NRF2 as a whole to identify the key controller and obtain an efficient increase in treatment sensitization. For this, this project will use single knockout U251MG lines for the ATG7 gene and, in an unprecedented way, for the LAMP2A gene, in addition to validating U251MG double knockout cells for ATG7 and LAMP2A. With this, this project aims to clarify the role of MA and CMA coordinated by the transcription factor NRF2, verifying the interaction between these processes and their impact on the response to chemotherapy in human glioblastoma. We believe that the results of this project can serve as a basis for improving the management of autophagy along with the modulation of NFR2 and thus contribute as an alternative therapy for glioblastoma and have approvals for future drug treatments for this purpose.

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