Current PhD opportunities
The School of Biosciences is please to announce funding for PhD studentships to start in September 2017
Investigating protein-protein interactions with application to host cell protein impurities in monoclonal antibody purification
Supervisor/s: Dr Mark Wass and Professor Daniel Bracewell, UCL
Protein-protein interactions have important roles in biological processes. However, nonspecific interactions can also occur, which are unwanted and can affect biological systems. This project will use structural bioinformatics approaches to investigate the nature of protein-protein interactions with application to the area of biotherapeutics. Non-specific interactions are a significant problem for the generation of biotherapeutics, such as monoclonal antibodies. Biotherapeutics are synthesised in cell cultures and proteins from the cells interact with the antibodies, such impurities need to be removed for the antibody to be suitable for use in treatment of disease. Host cell proteins represent a significant problem in the purification process as they are diverse representing the range of different proteins present in the host cell.
This project will primarily focus on the use of structural bioinformatics approaches to analyse the interactions of host cell proteins with biotherapeutics with the aim of identifying modifications to the antibodies or the purification processes that will reduce the level of host cell protein impurities. This will be followed up by wet laboratory experiments to validate the findings of the computational research.
The project will be supervised by Dr Mark Wass (University of Kent) and Prof Daniel Bracewell (UCL). The student will primarily be based in the School of Biosciences at the University of Kent and some elements of the project will be completed at UCL.
This project is ideally suited to a student with some experience of bioinformatics or computing. All candidates are expected to have a minimum of an upper 2nd class degree in an appropriate field.
This is a four year EPSRC funded project with a stipend at Standard Research Council rates (£14,553 for 2017/18). Applications can be made online at http://www.kent.ac.uk/bio/study/postgraduate/applications.html where the project title should be entered as the proposed area of research and Dr Mark Wass as supervisor. Please include a CV and cover letter explaining your interest in the project. Applications must be received by Friday 30th June. Interviews will be held at the University of Kent in July.
Informal enquiries can be addressed to Dr Mark Wass (firstname.lastname@example.org) or Prof Daniel Bracewell (email@example.com).
Funding: The studentship will pay an annual stipend at the UK Research Council rate of £14,553 (rate for 2017/2018) and cover tuition fees at the rate for UK/ EU students. To be eligible for a full award a student must have no restrictions on how long they can stay in the UK and have been ordinarily resident in the UK for 3 years prior to the start of the programme (for EU applicants this includes time spent studying).
Mapping the molecular mechanisms of chaperone-amyloid interaction
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.
Until recently, only the TSEs were believed to be infectious diseases via transmissible amyloid particles known as prions and typified by Creutzfeldt Jakob Disease in humans. New data are emerging, which suggest that the amyloid aggregates previously thought to be non-infectious (for example Abeta amyloid associated with AD), can propagate the disease state in the infected individual. How this propagation proceeds in vivo in disease is not known. It is this question we seek to answer in this project.
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 that explains the formation of small propagation competent seeds from large amyloid fibrils, 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.
- To develop methods to express and purify chaperones with known amyloid fragmentation activities.
- To develop imaging methods to quantify individual fibril particles during fibril fragmentation in the absence and presence of the purified chaperone proteins.
- 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 successful candidate is expected to be a highly motivated student with an interest in multidisciplinary research. He/she will be expected to have a 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, including the state-of-the-art high-resolution atomic force and super resolution microscopy imaging equipment in the Biosciences imaging facility. This project will provide the candidate with a broad multidisciplinary scientific training. .
The successful candidate will be based in Wei-Feng Xue’s and Mick Tuite’s research groups in the Kent Fungal Group (KFG) in School of Biosciences at the University of Kent (Canterbury campus). Informal enquiries can be addressed to Wei-Feng Xue (W.F.Xue@kent.ac.uk) or Mick Tuite (M.F.Tuite@kent.ac.uk).
HOW TO APPLY:
Applications can be made using the online University application page where the project title should be entered as the proposed area of research and Dr. Wei-Feng Xue as supervisor. Please include a CV and a cover letter. Applications must be received by Monday 26th June 2017.
RECENT RELEVANT REFERENCES:
- 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. Molecular Microbiology 104: 125-143.
- Speldewinde, S.H., Doronina, V.A., Tuite, M.F. & Grant, C.M. (2017). Disrupting the cortical actin cytoskeleton points to two distinct mechanisms of yeast [PSI+] prion formation. PLoS Genetics 13:e1006708.
- Al-Hilaly, Y.K., Biasetti, L., Blakeman, B, Pollack, S.J., Zibaee, S., Sada, A.A., Thorpe, J.R. Xue, W.-F., Serpell, L.C., The involvement of dityrosine crosslinking in a-synuclein assembly and deposition in Lewy Bodies in Parkinson’s disease, Sci Reports 6 (2016) 39171
- Sideri, T., Yashiroda, Y., Yoshida, M., Tuite, M.F. and Bähler, J. (2017). The copper transport-associated protein Ctr4 can form prion-like epigenetic determinants in Schizosaccharomyces pombe. Microbial Cell 4: 16 – 28.
- Tuite, M.F. (2016) Remembering the past: a new form of protein-based inheritance. Cell 167: 302-303
- Tuite, M.F. (2016) An acid tale of prion formation. eLife 5: e17978.
- Xue, W.-F., Nucleation: the birth of a new protein phase, Biophysics Journal 109 (2015) 1999- 2000.
- Tuite, M.F., Howard, M.J. and Xue, W.-F. (2014) Dynamic prions revealed by magic. Chemistry & Biology 21: 172-3.
- Marshall, K.E., Marchante, R.M.N., Xue, W.-F., Serpell, L.C. (2014) The relationship between amyloid structure and cytotoxicity. Prion 8: 1-5 ?
- Marchante, R.M.N., Rowe, M., Zenthon, Howard, M.J. and Tuite, M.F. (2013) Structural definition is important for the propagation of the yeast [PSI+] prion. Molecular Cell 50: 675– 685.
- Xue, W.-F., and Radford, S.E. (2013) An imaging and systems modeling approach to fibril breakage enables prediction of amyloid behavior. Biophysics Journal 105: 2811-2819.
Funding: The studentship will pay an annual stipend at the UK Research Council rate of £14,553 (rate for 2017/2018) and cover tuition fees at the rate for UK/ EU students. International applicants must make provision to meet the difference between Home and International fees. The studentship is offered as a Graduate Teaching Assistantship which requires the student to carry out a number of hours of teaching / teaching support duties in the School of Biosciences.
To apply: Please submit an on-line application via the University application page enter the project title as the proposed research topic and Dr Wei-Feng Xue as the supervisor. For the research proposal please enter "as advertised". Please include a cv and a covering letter.
Deadline: 27 June 2017