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MiRNAs expression by astrocytes cronically exposed to reactive oxygen species submitted to acute hypoxia

Grant number: 20/00110-4
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): September 01, 2020
Effective date (End): July 31, 2021
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal researcher:Marimélia Aparecida Porcionatto
Grantee:Natália Rodrigues Courbassier
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Hypoxia inducible factor (HIF) is a hypoxia responsive transcription factor activated by oxygen (O2) imbalance between tissue demand and supply. In reactive astrocytes HIF-1± upregulation is related to ischemic tolerance, or preconditioning. Preconditioning is an event capable of promoting resistance to a subsequent severe ischemic insult, by decreasing the injury area. The literature databases suggest that HIF-1± is able to promote preconditioning through the synthesis of neuroprotective effectors and/or molecules such as erythropoietin (EPO) and Vascular Endothelial Growth Factor (VEGF). It was observed that HIF-1± expression by reactive astrocytes depends on P2X7 receptor, an ion channel forming ATP receptor, whose expression is also upregulated, allowing ischemic tolerance induction. VEGF stimulates the proliferation mediated by endothelins on astrocytes, which in turn, activate the astrocytic receptors leading to proliferation through G1 phase cyclin upregulation. Another alteration on gene expression observed in astrocytes exposed to hypoxia consists on activation of Notch signaling pathway. Upregulation of Notch-1 is seen mainly on astrocytes that are GFAP+. microRNAs are important posttranscriptional modulators, that inhibit translation or increase mRNA degradation by biding to the 3' untranslated region (3'UTR). In the light of the above scenario, the present study aims to understand astrocytic response to hypoxia of mutant Nox3eqlb mouse, lineage that displays a point mutation in the NADPH oxidase 3 (Nox3) gene. This mutation leads to an increase in reactive oxygen species (ROS) production. Our hypothesis is that chronic exposition to ROS in Nox3eqlb mice is capable to promote preconditioning, protecting the cells from hypoxia. The project goal is to evaluate whether astrocytes isolated from Nox3eqlb, that are chronically submitted to a larger amount of ROS, presents higher resistance to hypoxia in vitro than wildtype astrocytes. To achieve this, we will use astrocytes isolated from the cortex of wildtype (BALB/c) and mutant (Nox3eqlb) mice. We will analyze expression of HIF-1± and GFAP using immunocytochemistry. Also, we will quantify cell proliferation, expression of miRNAs related to ischemia protection, and Notch signaling pathway target genes expression, on astrocytes submitted or not to hypoxia. We expect to verify whether chronic exhibition to ROS affects astrocytic molecular and cellular responses to hypoxia, especially related to preconditioning resistance ischemic promoter.

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