or
Continue with FacebookLooking to list your PhD opportunities? Log in here.
This project is no longer listed on FindAPhD.com and may not be available.
Click here to search FindAPhD.com for PhD studentship opportunities
Dr A MacDonald
Prof N J Stonehouse
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Background: HPV infections are associated with diseases that impact both sexes including cervical cancer and head and neck squamous cell carcinoma (HNSCC). Despite the availability of a vaccine, current projections suggest that HPV-associated disease rates will not reduce significantly for several decades. To identify novel therapeutic targets that augment the vaccination strategy, it is vital to gain a greater understanding of the fundamental biology of HPV.
HPV infection differs significantly from that of other viruses as it is tied to the differentiation status of the infected keratinocyte. Virions target proliferating basal stem cells in the epithelium, whilst virus-encoded proteins transform the hostile environment of the keratinocyte into one conducive for chronic infection. We identified the HPV E5 protein as a driver of unscheduled DNA replication and a delay in keratinocyte differentiation, both of which are required for efficient HPV replication in terminally differentiated keratinocytes. The proposed research will decipher the molecular basis for these observations.
Objectives: Combine primary cell culture models (raft cultures) with a genetic/cellular approach to study the role of the E5 protein in the HPV lifecycle.
1. Mutagenesis of E5 sequences within the HPV genome and impact on cell cycle control and differentiation using raft cultures.
2. Study the contribution of host signaling pathways to these processes using small molecule inhibitors and expression of dominant active/negative mutants.
3. Lentiviral expression of E5 in keratinocytes followed by detailed characterization of E5-host interactions, including critical host binding partners.
Timeliness: HPV-related diseases are increasing despite the vaccine. There is a need to develop therapeutic intervention strategies, which will be improved with a greater understanding of the virus lifecycle.
The Macdonald group at Leeds:
Macdonald is an Associate Professor and a recipient of the Promega Young Microbiologist of the Year award. He runs a rapidly expanding research group that specializes in the study of chronic virus infections, in particular those caused by small DNA tumour viruses. The group occupies modern space equipped for state of the art molecular virology, physiology and cell biology studies. They routinely publish in leading international peer reviewed journals including PNAS and PLoS Pathogens. As a graduate student within this group the successful applicant would be expected to contribute to towards high impact publications.
HPV infection differs significantly from that of other viruses as it is tied to the differentiation status of the infected keratinocyte. Virions target proliferating basal stem cells in the epithelium, whilst virus-encoded proteins transform the hostile environment of the keratinocyte into one conducive for chronic infection. We identified the HPV E5 protein as a driver of unscheduled DNA replication and a delay in keratinocyte differentiation, both of which are required for efficient HPV replication in terminally differentiated keratinocytes. The proposed research will decipher the molecular basis for these observations.
Objectives: Combine primary cell culture models (raft cultures) with a genetic/cellular approach to study the role of the E5 protein in the HPV lifecycle.
1. Mutagenesis of E5 sequences within the HPV genome and impact on cell cycle control and differentiation using raft cultures.
2. Study the contribution of host signaling pathways to these processes using small molecule inhibitors and expression of dominant active/negative mutants.
3. Lentiviral expression of E5 in keratinocytes followed by detailed characterization of E5-host interactions, including critical host binding partners.
Timeliness: HPV-related diseases are increasing despite the vaccine. There is a need to develop therapeutic intervention strategies, which will be improved with a greater understanding of the virus lifecycle.
The Macdonald group at Leeds:
Macdonald is an Associate Professor and a recipient of the Promega Young Microbiologist of the Year award. He runs a rapidly expanding research group that specializes in the study of chronic virus infections, in particular those caused by small DNA tumour viruses. The group occupies modern space equipped for state of the art molecular virology, physiology and cell biology studies. They routinely publish in leading international peer reviewed journals including PNAS and PLoS Pathogens. As a graduate student within this group the successful applicant would be expected to contribute to towards high impact publications.
Funding Notes
4 year BBSRC studentship, under the White Rose Mechanistic Biology DTP. The successful applicant will receive fees and stipend (c.£13863 for 2014-15). The PhD will start in Oct 2015. Applicants should have, or be expecting to receive, a 2.1 Hons degree in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. There are 2 stages to the application process.
Please see our website for more information:
http://www.fbs.leeds.ac.uk/gradschool/keywords/mnuFindaphd.php
Please see our website for more information:
http://www.fbs.leeds.ac.uk/gradschool/keywords/mnuFindaphd.php
References
Some recent publications from the Macdonald group.
1. Muller, Prescott, Wasson and Macdonald (2015). Human papillomavirus E5 oncoprotein: function and potential target for anti-viral therapeutics. Future Virology. In press.
2. Knight, Stakaityte, Abdul-Sada, Blair, Stevens, Macdonald, Blackbourn and Whitehouse (2015). Merkel cell polyomavirus small T antigen mediates microtubule destabilisation to promote cell motility and migration. Journal of Virology. In Press.
3. Richards, Doble, Wasson, Blair, Wittmann and Macdonald (2014). Human Papillomavirus E7 Oncoprotein Increases Production of the Anti-Inflammatory Interleukin-18 Binding Protein in Keratinocytes. Journal of Virology.
4. Griffiths, Abdul-Sada, Knight, Jackson, Richards, Prescott, Peach, Blair, Macdonald*, Whitehouse* (2013). Merkel cell polyomavirus small T antigen targets the NEMO adaptor protein to disrupt inflammatory signalling. Journal of Virology 87(24):13853-67
5. Wetherill, L., Holmes, K., Verow, M., Muller, M., Howell, G., Harris, M., Stonehouse, N., Fishwick, C., Foster, R., Blair, G.E., Griffin, S. & Macdonald, A. High-risk human papillomavirus E5 oncoprotein displays channel-forming activity sensitive to a novel small molecule inhibitor. Journal of Virology 86(9): 5341-51.
6. McFadden, N., Bailey, D., Carrara, G., Benson, A., Chaudhry, Y., Shortland, A., Heeney, J., Yarovinsky, F., Simmonds, P., Macdonald, A. and Goodfellow, I. (2011). Norovirus Regulation of the Innate Immune Response and Apoptosis occurs via the Product of the Alternative Open Reading Frame 4. PLoS Pathogens Dec; 7(12):e1002413.
7. Mankouri, J., Fragkoudis, R., Richards, K.R., Wetherill, L., Harris, M., Kohl, A., Elliott, R.M. & Macdonald, A. (2010). The nemo-related protein optineurin is a regulator of innate antiviral signalling. PLoS Pathogens 19; 6(2):e1000778.
1. Muller, Prescott, Wasson and Macdonald (2015). Human papillomavirus E5 oncoprotein: function and potential target for anti-viral therapeutics. Future Virology. In press.
2. Knight, Stakaityte, Abdul-Sada, Blair, Stevens, Macdonald, Blackbourn and Whitehouse (2015). Merkel cell polyomavirus small T antigen mediates microtubule destabilisation to promote cell motility and migration. Journal of Virology. In Press.
3. Richards, Doble, Wasson, Blair, Wittmann and Macdonald (2014). Human Papillomavirus E7 Oncoprotein Increases Production of the Anti-Inflammatory Interleukin-18 Binding Protein in Keratinocytes. Journal of Virology.
4. Griffiths, Abdul-Sada, Knight, Jackson, Richards, Prescott, Peach, Blair, Macdonald*, Whitehouse* (2013). Merkel cell polyomavirus small T antigen targets the NEMO adaptor protein to disrupt inflammatory signalling. Journal of Virology 87(24):13853-67
5. Wetherill, L., Holmes, K., Verow, M., Muller, M., Howell, G., Harris, M., Stonehouse, N., Fishwick, C., Foster, R., Blair, G.E., Griffin, S. & Macdonald, A. High-risk human papillomavirus E5 oncoprotein displays channel-forming activity sensitive to a novel small molecule inhibitor. Journal of Virology 86(9): 5341-51.
6. McFadden, N., Bailey, D., Carrara, G., Benson, A., Chaudhry, Y., Shortland, A., Heeney, J., Yarovinsky, F., Simmonds, P., Macdonald, A. and Goodfellow, I. (2011). Norovirus Regulation of the Innate Immune Response and Apoptosis occurs via the Product of the Alternative Open Reading Frame 4. PLoS Pathogens Dec; 7(12):e1002413.
7. Mankouri, J., Fragkoudis, R., Richards, K.R., Wetherill, L., Harris, M., Kohl, A., Elliott, R.M. & Macdonald, A. (2010). The nemo-related protein optineurin is a regulator of innate antiviral signalling. PLoS Pathogens 19; 6(2):e1000778.
How good is research at University of Leeds in Biological Sciences?
Research output data provided by the Research Excellence Framework (REF)
Click here to see the results for all UK universitiesProject supervisors
Dr A MacDonald's profile is coming soon
View other supervisors at University of LeedsCareer overview
Professor Nicola Stonehouse is a virologist with a focus on the fundamental aspects of the viral lifecycle and the development of novel vaccines. She completed her BSc at the University of East Anglia and obtained her PhD in 1992 from the University of Leeds. As a post-doctoral fellow, she developed an interest in high-resolution structural studies of RNA-protein complexes, which led to a long-term collaboration with Lars Liljas’ group in Uppsala, Sweden. This collaboration ultimately resulted in the award of a Career Development Fellowship from the UK Medical Research Council. Over the years, Professor Stonehouse transitioned from working on bacteriophage to picornaviruses and was appointed as Lecturer in 2001, subsequently becoming Chair in Molecular Virology in 2014. She collaborates widely, with current funding supporting vaccine development, studies of the replication of foot-and-mouth disease virus, and understanding the fundamental aspects of viral capsid assembly. Her vaccine projects involve generating a generic vaccine ''scaffold'' and developing stabilised empty viral capsids as vaccine candidates for poliovirus and other enteroviruses. Professor Stonehouse is a Fellow of the Royal Society of Biology (FRSB), the Royal Society for the encouragement of Arts, Manufacture and Commerce (FRSA), and the UK Higher Education Academy. She teaches at all levels and has taken on various roles to support junior scientists.
Research interests
Professor Stonehouse''s research focuses on viral replication and assembly, as well as vaccine development. She is particularly interested in the fundamental aspects of the viral lifecycle and the development of novel vaccines. Her work includes studies on the replication of foot-and-mouth disease virus and understanding the fundamental aspects of viral capsid assembly. Current projects involve the development of a generic vaccine scaffold and the characterisation of stabilised empty viral capsids as vaccine candidates for poliovirus and other enteroviruses. Additionally, she has a background in high-resolution structural studies of RNA-protein complexes and has collaborated on various projects related to picornaviruses.
Molecular Virology
Virus-Like Particle Vaccines
Virus Replication
Virus Assembly
Foot-and-Mouth Disease Virus
Poliovirus
RNA Biology
Vaccine Development
Structural Biology
Picornaviruses
Viral Capsid Assembly
RNA-Protein Complexes
High-Resolution Structural Studies
Infectious Diseases
Postgraduate Research
Picornaviral Replication
RNA Aptamers
Vaccine Platforms
Live Cell Imaging
Mass Spectrometry
Enterovirus Maturation
Find a scholarship to fund your dream Masters
Sign in to view and filter all scholarship opportunities
or
Continue with Facebook