Elucidation of the molecular pathways responsible for human cytomegalovirus reactivation as a paradigm for therapeutic intervention

The Department of Medicine is seeking applications from eligible students who wish to undertake an MRC-funded 3 year PhD studentship starting October 2012. The five research projects available, together with supervisor details, can be found on the Departments website at: http://www.med.cam.ac.uk/mrc-phd-studentship-2012-project-outlines/

A major cause of disease in a number of immune-compromised populations, the molecular mechanisms responsible for human cytomegalovirus (HCMV) reactivation are still not fully understood. Currently, the working model for HCMV is that latency is established in a pluripotent pool of haematopoietic cells resident in the bone marrow. Despite the pluripotency of the progenitor, HCMV carriage is observed predominantly in the cells of the myeloid lineage with reactivation occurring upon terminal differentiation of these cells. As such, my current research is aimed at identifying the dual role myeloid cell differentiation and concomitant activation of inflammatory signalling plays in HCMV reactivation in dendritic cells (DCs).

The pivotal event (at a molecular level) for HCMV reactivation is the transition of the major lytic promoter (MIEP) from a silenced to an active state and current data suggests the activation of cellular signalling is crucial for this. It is hypothesized that this is not a linear event and this project seeks to address the contribution of different signalling pathways on HCMV reactivation and the cross-talk that occurs between them in the context of HCMV but with potentially wider implications for cell biology. As well as using models of HCMV latency in the laboratory to address these pathways using established techniques other specific aspects will include the use of recombinant HCMVs in which the CREB/ATF, NF-kB and IFN response elements have been deleted from the MIEP to address the relative impact of downstream molecular targets of the signalling pathways that trigger HCMV reactivation. A second aspect will take advantage of our recent observations that subsets of myeloid DCs respond differentially to reactivation signals depending on maturation status. Suggestive that the presence (or absence) of specific cellular proteins are required for signalling pathways to be pro-reactivation which will be addressed using comparative proteomics which, in itself, could yield new insight into the pathways analysed as well as furthering the specific aims of the research. Overall this project would expose the student to a wide range of techniques and will provide training in the areas of virology, molecular biology, cell signalling and DC immunology.

Post short-list enquiries can be made to Professor Edwin Chilvers ([Email Address Removed]).

Fixed-term: The funds for this studentship are available for 3 years in the first instance.

The University values diversity and is committed to equality of opportunity. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.

Applicants should submit a full CV, including details of two referees, and a covering letter clearly indicating which of the projects they are interested in to Mrs Linda Whyles via email: [Email Address Removed].
Applications must be received by 5pm on the closing date.

Quote reference: RC00092, Closing date: 19 February 2012