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PhD in Medicine Targeting Neuroinflammation in Mtorc1-driven Brain Tumours

Cardiff University is pleased to invite applicants to apply for a new opening PhD position in bioinformatics. Eligible candidates should submit the applications before February 28, 2019.

This project will not only create a new brain tumour model, but will also give us valuable information on mTOR's involvement in the development of brain tumours.

Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a common occurrence in cancer, which enhances cell growth and survival. Brain tumours take advantage of mTORC1 to drive many 'hall-marks' of cancer. There is a clear need to generate new model systems to explore mTORC1-hyperactivation in the brain, where such models will allow us to better understand how mTORC1 impacts oncogenic processes in different brain cell lineages.

To create a new and flexible mTOR-active brain model, we will knock out the Tuberous Sclerosis Complex genes, TSC1 and TSC2, by CrispR in isogenic human stem cell lines. These will be differentiated into various brain cell lineages (such as neurons, astrocytes and glial cells), and tested for mTORC1 activity, cell growth/proliferation, pro-inflammatory gene expression, and, in neurons, synaptogenesis. We will characterise the inflammatory response in these mTOR-active brain models, seeking to determine the molecular mechanisms underlying neoplastic disease. To do this, we will characterise the transcriptome of these mTORC1-active brain cells using RNA-Seq and use bioinformatic approaches to unravel mTORC1-mediated transcriptional regulation, with focus on type 1 interferon signalling, NLRP3 inflammasome and STAT3.

By combining genetic analysis with computational techniques, we will determine the consequences of mTORC1 hyperactivation on brain cell behaviour. We will examine whether cytosolic mitochondrial DNA or reactive oxygen species contribute to the observed inflammatory response. Finally, we will assess drugs that target inflammatory pathway as potential treatments for mTORC1-driven brain tumours.


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