Start Date: 20/09/21
Division: Cellular Medicine
High-grade gliomas are complex and devastating tumours that resist multi-modal therapies with survival times of ~14 months. Macrophages and microglia promote glioma growth, however how they achieve their tumour-promoting activity is unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated in macrophages by the mitochondrial immunometabolite itaconate upon up-regulation of inducible immunoresponsive gene 1 (IRG1) and inhibits production of pro-inflammatory cytokines. This project will test the hypothesis that association with tumour cells causes upregulation of IRG1 in tumour-associated macrophages/microglia, increasing the levels of itaconate, which in turn activates Nrf2, creating immunosuppressive microenvironment. We aim to understand: (i) What are the molecular mechanisms by which association with glioma cells activate Nrf2 in macrophages/microglia? (ii) How does Nrf2 affect the interactions between glioma cells and macrophages/microglia? To answer these questions, Nrf2 will be manipulated genetically or pharmacologically in macrophages/microglia grown in glioma-conditioned medium. We will quantify the expression of pro- and anti-inflammatory genes. A co-culture system will be used to assess glioma cell proliferation, migration and invasion. We will perform multiplex immunofluorescence in human glioma tumours and quantify the levels of IRG1, Nrf2, and its classical target, NOQ1. If, as hypothesized, we find higher IRG1 and Nrf2/NQO1 expression in tumour-associatedmacrophages/microglia, we will correlate this expression with the histopathological characteristics of the tumours and patient prognosis. Detailed understanding of the role of Nrf2 in glioma microenvironment will allow to inhibit the pro-tumoural activity of macrophages/microglia. The availability of compounds synthetically lethal with hyperactive Nrf2 will facilitate clinical translation of our findings.
Applicants to complete the Application form and email to [Email Address Removed] along with a CV and 2 academic references by Monday 22nd March 2021.
First class honours degree, and/or a Masters degree in a relevant discipline. (Non-clinical applicants)
MBChB (clinical applicants)
English language requirements
IELTS minimum overall score of 6.5
Reading 5.5, Listening 5.5, Speaking 5.5 Writing 6.0