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Understanding the role of DRAM in infection and autophagy-related disease

  • Full or part time
  • Application Deadline
    Wednesday, January 29, 2020
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

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 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, @jasonkinglab

Phil Elks lab: http://www.elkslab.weebly.com, @elkslab_sheff

Starting a PhD is an exciting time, and a substantial 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.

Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.

Funding Notes

This position is open to self-funded students and also has the possibility of being funded by a fees scholarship, further details can be found here: View Website

First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link: View Website

All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.

References

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

How good is research at University of Sheffield in Biological Sciences?

FTE Category A staff submitted: 44.90

Research output data provided by the Research Excellence Framework (REF)

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