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What role do potassium ions play in the trafficking and function of proteins in the endocytic pathway?


   Faculty of Biological Sciences


About the Project

What role do potassium ions play in the regulation of the endocytic pathway?

The endocytic pathway plays a central role in cellular physiology. It is how many nutrients are taken up by the cell, it plays a central role in receptor signalling and downregulation and its end point, the lysosome, is a major site for the degradation of endocytosed macromolecules. The importance of the endocytic pathway is underlined by the fact that many viruses use this as an entry route when they infect cells. Yet there is still much to learn about endocytosis and how it is regulated. This includes the focus of this project: what is the role of endosomal ion channels and ions?

Our recent work has established that potassium ions and ion channels in the endosomal pathway are required for the infection of cells by a number of viruses and may promote conformational changes in viral fusion proteins. Despite this, we know very little about the roles of these potassium channels and ions in the normal cellular functions. Clearly viruses are telling us something important about potassium channels and ions in the endocytic pathway. We now want to determine whether endosomal potassium ions plays an important role in the regulation of the endocytic pathway.

This project will explore whether potassium ions are required for the uptake of nutrients into cells, the downregulation of plasma membrane receptors and the breakdown of macromolecules by lysosomes.

The project will use an array of techniques including fluorescence microscopy, subcellular fractionation, proteomics, gene knockdowns and treatment of cells with specific channel inhibitors to probe what happens when ion channels responsible for potassium import into endosomes are inhibited. This will not only provide new insights into cellular physiology, but may also help us understand why many viruses need endosomal potassium when they infect cells. 

The project will be jointly supervised by Eric Hewitt a cell biologist with expertise in the endocytic pathway, John Barr a virologist whose work led to the identification of a role of potassium ions in viral infection and Jon Lippiat a physiologist with expertise in ion channels.  This enables the project to use a multidisciplinary approach to study the role of endosomal potassium ion channels and the PhD student will gain expertise in techniques that span these disciplines. 

Further information about the the supervisory team can be found on their websites and more information about the work leading up to this project and the supervisors expertise can be found in the references below.

https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/84/dr-eric-hewitt

https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/22/dr-john-n-barr

https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/103/dr-jonathan-lippiat

Funding Note

Self-funded students: International or domestic self-funded or scholarship/fellowship PhD students are always welcome to apply. International students must have a good command of both written and spoken English. In addition to University fees, laboratory fees will be required if you are self-funded. Applications can be made throughout the year.

For information about how to apply for this PhD project, please go to the Faculty of Biological Sciences website

https://biologicalsciences.leeds.ac.uk/research-degrees

https://biologicalsciences.leeds.ac.uk/research-degrees/doc/how-to-apply

Eligibility: 

You should hold a first degree equivalent to at least a UK upper-second class honours degree or a MSc degree in a relevant subject. This project would suit someone with a strong background in tissue engineering, cancer biology or closely-related areas. Additional experience of conducting research in a multidisciplinary setting is highly desirable. Upon completion of the PhD, the successful candidate will be uniquely equipped for high-demand careers within academia or industry with desirable skills in bioengineering, regenerative medicine and cancer/cell biology.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Biological Sciences minimum requirements in IELTS and TOEFL tests are:

  • British Council IELTS - score of 6.0 overall, with no element less than 5.5
  • TOEFL iBT - overall score of 87 with the listening and reading element no less than 20, writing element no less than 21 and the speaking element no less than 22.

How to apply:

To apply for this project applicants should complete an online application form and attach the following documentation to support their application. 

  • a full academic CV
  • degree certificate and transcripts of marks
  • Evidence that you meet the University's minimum English language requirements (if applicable).
  • Evidence of funding

To help us identify that you are applying for this project please ensure you provide the following information on your application form;

  • Select PhD in Biological Sciences as your programme of study
  • Give the full project title and name the supervisors listed in this advert

Funding Notes

Self-funded students: International or domestic self-funded or scholarship/fellowship PhD students are always welcome to apply. International students must have a good command of both written and spoken English. In addition to University fees, laboratory fees will be required if you are self-funded. Applications can be made throughout the year.

References

REVIEW ARTICLE
Charlton FW, Pearson HM, Hover S, Lippiat JD, Fontana J, Barr JN, Mankouri J. 2020. Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives. Viruses. 12: 844

RESEARCH PAPERS FROM THE SUPERVISORS' LABS
Pearson H, Todd EJAA, Ahrends M, Hover SE, Whitehouse A, Stacey M, Lippiat JD, Wilkens L, Fieguth H-G, Danov O, Hesse C, Barr JN, Mankouri J. 2021. TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection. Thorax. 76: 64-7
Cole BA, Johnson RM, Dejakaisaya H, Pilati N, Fishwick CWG, Muench SP, Lippiat JD. 2020. Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel. iScience. 23: 101100
Charlton FW, Hover S, Fuller J, Hewson R, Fontana J, Barr JN, Mankouri J. 2019. Cellular cholesterol abundance regulates potassium accumulation within endosomes and is an important determinant in bunyavirus entry. Journal of Biological Chemistry. 294: 7335-7347
Hover S, Foster B, Fontana J, Kohl A, Goldstein SAN, Barr JN, Mankouri J. 2018. Bunyavirus requirement for endosomal K+ reveals new roles of cellular ion channels during infection. PLoS Pathogens. 14: :e1006845
Punch EK, Hover S, Blest HTW, Fuller J, Hewson R, Fontana J, Mankouri J, Barr JN. 2018. Potassium is a trigger for conformational change in the fusion spike of an enveloped RNA virus. Journal of Biological Chemistry. 293. 9937-9944
Casey, T.M., Meade, J.L. and Hewitt, E.W. (2007) Organelle proteomics: identification of the exocytic machinery associated with the natural killer cell secretory lysosome. Mol. Cell. Proteomics. 6, 767-80
Jakhria T, Hellewell AL, Porter MY, Jackson MP, Tipping KW, Xue WF, Radford SE, Hewitt EW. (2014). β2-Microglobulin Amyloid Fibrils Are Nanoparticles That Disrupt Lysosomal Membrane Protein Trafficking and Inhibit Protein Degradation by Lysosomes. J Biol Chem. 289:35781-94

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