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Precision Medicine DTP - How do IFITM proteins regulate the Interferon Related DNA-damage Resistance Signature (IRDS) and clinical outcomes in cancers of high unmet clinical need?

  • Full or part time


    Dr S Wilson
  • Application Deadline
    Wednesday, January 08, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Background

Interferon Induced Transmembrane proteins (IFITMs) are a family of innate immune membrane proteins that can inhibit viral infection at cell entry (e.g. HIV, influenza A virus, Ebola virus), but are commonly found to be elevated in certain cancers (e.g. cervical, ovarian, oesophageal, glioblastoma). The links between these two distinct biomedical contexts have previously been obscure. Our recently published data shows that IFITMs can block HIV translation, while similar data from whole-cell and pulse-SILAC proteomic analysis together with RNA analysis shows that IFITMs can regulate a subset of cellular mRNAs leading to their enhanced or diminished expression in tumours. This latter process leads to a distinct pattern of gene expression termed the Interferon related DNA-damage resistance signature (IRDS) and is associated with therapeutic resistance (including interferon insensitivity), as well as clinical severity. Further, immunohistochemistry of tumour microarrays shows distinct patterns of IFITM localisation that can be used to segregate glioblastoma (GMB) patients into distinct groups. We have seen that IFITM-driven effects on translation are enhanced when membrane and endosomal localisation is lost; similarly in cancer cells, the localisation of IFITMs affects both the clonogenicity of tumour cells and their rate of their proliferation. The localisation and antiviral function of IFITM proteins at cell entry is known to be regulated through post-translational modifications (phosphorylation, palmitoylation and ubiquitination), but it is not known how these modifications influence the new found ability of IFITMs to regulate gene expression, IRDS expression and interferon insensitivity.

Aims

The overall aim of this project will be to study how post-translational modifications regulate IFITM sub-cellular localisation and lead to alterations in the pattern of expression of cellular mRNAs, and so modulate the IRDS and interferon sensitivity. This will be thorough the use of RNA-Seq, proteomics, imaging, TMA analysis, and molecular cell biology in GBM, a cancer of very high unmet clinical need which is a strategic priority in the UK and is a focus of major cancer researcher efforts in Edinburgh (https://www.ed.ac.uk/cancer-centre).

1. This will be achieved by first screening a panel of IFITM alleles with alterations in defined sites of phosphorylation, palmitoylation and ubiquitination overexpressed in GBM cell lines or introduced into the endogenous gene using CRISPR/Cas9 technology, to determine sub-cellular localisation via microscopy-based approaches.

2. These alleles will then be tested for their ability to regulate cellular RNAs and proteins through qPCR, RNA sequencing, ribosomal profiling and pulse-SILAC mass spectrometry. Interactions with cellular translational machinery will be defined via affinity proteomics.

3. These data will be correlated with similar analyses in patient derived GBM stem cell lines to measure IFITM post-translational modification and gene expression allowing links to be made between IFITM modification, sub-cellular localisation, interferon sensitivity, therapeutic resistance, and clinical outcomes in patients.

Collectively, such data will allow patient stratification to be made based on IFITM localisation or IRDS expression signatures. It will also reveal in molecular detail how IFITM proteins can regulate cellular gene expression and viral replication, feasibly allowing new therapeutic strategies or diagnostics to be proposed for either viral disease or other forms of cancer in which IFITM expression, interferon sensitivity, or IRDS is a defining feature.

Training outcomes

Full training will be given in a range of molecular, cellular, genomic and proteomic level techniques in the context of cancer cell biology and immunology, these include; eukaryotic cell culture, gene cloning and mutagenesis, CRISPR/Cas9 gene editing, western blot, confocal microscopy, PCR, qPCR, RNA-sequencing, ribosome/polysome profiling, and mass spectrometry. They will also acquire bioinformatics skills in the analysis of large data sets using, for example, MaxQuant (proteomic data) and CLC genomics workbench (RNA-Seq).

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2020

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area.
Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,009 (RCUK rate 2019/20) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. IFITM proteins inhibit HIV-1 protein synthesis. Lee WY, Fu RM, Liang C, Sloan RD. (2018). Scientific Reports. 8(1):14551.

2. The effects of IFITM1 and IFITM3 gene deletion on IFNγ stimulated protein synthesis. Gómez-Herranz M, Nekulova M, Faktor J, Hernychova L, Kote S, Sinclair EH, Nenutil R, Vojtesek B, Ball KL, Hupp TR. (2019). Cell Signal. 60:39-56.

3. Fundamental properties of the mammalian innate immune system revealed by multispecies comparison of type I interferon responses. Shaw AE, Hughes J, Gu Q, Behdenna A, Singer JB, Dennis T, Orton RJ, Varela M, Gifford RJ, Wilson SJ, Palmarini M. (2017). PLoS Biol. 15(12):e2004086.

4. More than meets the I: the diverse antiviral and cellular functions of interferon-induced transmembrane proteins. Shi G, Schwartz O, Compton AA. (2017). Retrovirology. 14(1):53.

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