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Mapping the molecular mechanisms of chaperone-catalysed division of amyloid fibrils


Project Description

PhD STUDENTSHIP STARTING Sept 2019
LOCATION: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury

How do molecular chaperones interact and fragment amyloid fibrils in cells? This is the central question that this PhD project will address. Amyloid is an aggregated state of proteins associated with a number of devastating human disorders, for example Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes, and transmissible spongiform encephalopathies (TSEs). Amyloid diseases account for increasing medical and social importance, for example, more than half million people are suffering from AD in the UK alone, and PD affects about 1% of the population over the age of 60.

However, far from all amyloid types are linked to disease as some are tolerated by cells or even perform important biological functions in wide range of organisms from bacteria to mammals. For example, in yeast, Sup35 is a prion protein that functions as an epigenetic switch and information carrier, and the amyloid state of Sup35 is propagated between cells through division of the amyloid structures catalysed enzymatically by a group of proteins called chaperones. How amyloid propagation proceeds in vivo and how their propagation in disease differ from propagation of non-disease associated amyloid is not known. These are the questions we seek to answer in this project.

PROJECT OUTLINE:
The supervisors, Wei-Feng Xue and Mick Tuite are both core members of the Kent Fungal Group (KFG), running well-funded and well-equipped labs in the School of Biosciences at the University of Kent. They have long standing research interest in the formation of amyloid and the propagation of prions. Previous work by WFX and MFT has independently highlighted a fibril fragmentation mechanism of how transmission of amyloid might occur. WFX has developed a quantitative model of fibril fragmentation, and has developed AFM imaging methods to study these events and seeds. MFT has long standing expertise in the yeast prion protein Sup35, and how the amyloid form of Sup35 can propagate in vivo in yeast to confer the heritable [PSI+] phenotype through the enzymatic fragmentation action of the chaperone machinery involving Hsp104, 70 and 40.
The project will be centred on the following objectives.
A) To develop and optimise methods for recombinant expression and purification of chaperones with known amyloid fragmentation activities.
B) To develop nano-scale imaging methods to quantify individual fibril particles during fibril fragmentation in the absence and presence of the purified chaperone proteins.
C) To delineate the molecular mechanism of enzymatic Sup35NM amyloid fibril fragmentation. Sup35NM is a well-established yeast prion amyloid model system in our research programmes.

THE CANDIDATE:
The successful candidate is expected to be a highly motivated student with an interest in multidisciplinary research. He/she will be expected to have an undergraduate (BSc) degree at 2(i) or higher in Biochemistry, Biophysics, Biotechnology, Bioengineering, Biology, Biomedical Science, Chemistry or Chemical Engineering. The candidate will have the access to a range of protein biochemistry, microscopy, molecular and cell biology, computational modelling, and biophysical methods. This project will provide the candidate with a broad multidisciplinary scientific training. Informal enquiries can be addressed to Wei-Feng Xue () or Mick Tuite ().

ONLINE APPLICATION:
Applications can be made online where the project title should be entered as the proposed area of research and Dr. Wei-Feng Xue as main supervisor. Please include a CV and a cover letter explaining what motivates you to apply for this studentship. Applications must be received by Monday 4th February 2019.

FUNDING NOTES:
This is a funded studentship, which provides a stipend at the full UK Research Council rate of £14,777 (rate for 2018/19) plus tuition fees at the Home/EU rate. International applicants should make provision to meet the difference between Home /EU tuition fees and the international tuition fees. This is funded by the Graduate Teaching Assistantship (GTA), which provides financial support in return for 96 hours of teaching per year. For further information on the Graduate Teaching Assistantship scheme go to: https://www.kent.ac.uk/scholarships/search/FNADGTA00001

RECENT RELEVANT REFERENCES:
Marchante, R., Beal, D. M., Purton T. J., Tuite, M.F. and Xue, W.-F., The physical dimensions of amyloid aggregates control their infective potential as prion particles, eLife 6 (2017) e27109

Ness, F., Cox, B.S., Wongwigkarn, J., Naeimi, W.R. and Tuite, M.F. (2017) Overexpression of the molecular chaperone Hsp104 results in malpartition of [PSI+] propagons. Mol Microbiol (2016) 104: 125-143.

Funding Notes

£14,777 (2018/19 rate) plus Home/EU fees. See View Website

Scholarships will be offered at the standard UK Research Councils’ rate and administered under the Graduate Teaching Assistant Scheme (GTA).

UK, EU and overseas fee paying students are invited to apply. International applicants should make provision to meet the difference between Home /EU and International fees. Please note that overseas students must have the appropriate documentation to evidence eligibility to work in the UK.

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

FTE Category A staff submitted: 24.20

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

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