Intracellular degradation by lysosomes is important in a wide range of diseases. The capture and degradation of cytoplasmic components by autophagy allows tumour cells to survive starvation and neurons to remove the protein aggregates associated with neurodegeneration. The lysosomes which mediate this degradation also enable immune cells to kill pathogens and therefore suppress infections.
The aim of this project is to understand how lysosomes are regulated to protect cells from pathogens, starvation and misfolded proteins. Specifically, we want to understand the role of the protein DRAM (Damage Regulated Autophagy Modulator), an important lysosomal protein implicated in several diseases. In cancer, DRAM1 mediates regulation of autophagy and cell death by the tumour suppressor p53, and is decreased in many primary tumours. DRAM upregulation also aids the clearance of intracellular bacteria during models of tuberculosis infection. However, how DRAM regulates lysosomal activity and autophagy is unknown.
This project will use a combination of Dictyostelium and zebrafish models to understand how autophagy and pathogen killing is regulated at both the cellular and whole-organism levels. This will provide important new insight into the function of this key disease related protein and the underlying biology of how cells protect themselves.
You, the student, will be trained in a unique combination of both cell biology and in vivo techniques to take advantage of both cellular and zebrafish models of phagocyte biology and mycobacterial infection. This will include molecular biology techniques (CRISPR, protein fusions and overexpression), biochemistry, proteomics and live cell microscopy using the cutting-edge facilities at Sheffield. You will be part of a friendly, well-funded and successful team with extensive technical expertise, and will be encouraged to take advantage of the wealth of training opportunities offered by the MRC DiMEN doctoral training programme.
Further information on our research groups can be found on our lab webpages:
Jason King lab: http://www.king.group.shef.ac.uk
Phil Elks lab: http://www.elkslab.weebly.com
Starting a PhD is an exciting time, and a substantial 3.5-year commitment. If you are interested, we would strongly recommend getting in contact for an informal chat first to get a better feel for the project and any help you might need with the application.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. Cell. 2006 Jul 14;126(1):121-34.
The DNA damage-regulated autophagy modulator DRAM1 links mycobacterial recognition via TLP-MYD88 to authophagic defense. Van Der Vaart, M., Korbee, C. J., Lamers, G. E. M., Tengeler, A. C., Hosseini, R., Haks, M. C., … Meijer, A. H. (2014). Cell Host and Microbe. 2014. 15(6), 753-767.
PIKfyve/Fab1 is required for efficient V-ATPase and hydrolase delivery to phagosomes, phagosomal killing, and restriction of Legionella infection CM Buckley, VL Heath, A Gueho, C Bosmani, P Knobloch, P Sikakana, N Personnic, SK Dove, RH Michell, R Meier, H Hilbi, T Soldati, RH Insall† and JS King†. PloS pathogens. 15 (2), e1007551