Funding and Finance

MRes/PhD Studentship - Development of a Strategy to Modulate Senescence-induced Chronic Inflammation in the Transplanted Liver

  • Institute of Cellular Medicine
  • Reference Code: ICM83

Details:

Supervisors: Professor John A Kirby, Dr Simi Ali, Dr Graeme O’Boyle
Institute: Institute of Cellular Medicine
Sponsor: MRC and Newcastle Biomedical Research Centre
Duration of the award: 4 years (MRes Medical and Molecular Biosciences followed by a three-year PhD)

The processes associated with liver transplantation can accelerate the normal ageing process of bile ducts in transplanted livers, leading to cellular senescence. We have pilot data showing that some of this excess ageing is caused by inflammatory damage which can occur during the immunological rejection process. Recent studies have suggested that the processes of cellular senescence are themselves inflammatory by stimulating the release of chemotactic cytokines. These “chemokines” can recruit further immune cells to penetrate the graft tissues. This additional inflammation may then increase liver senescence by establishing a graft-damaging positive feedback loop.

In this project we will investigate the range and biological activity of chemokines produced by senescent biliary epithelial cells (cholangiocytes). This will be followed by development of an exciting new in vitro assay system which will allow live cell imaging under conditions which model blood flow. This will be used to demonstrate how the chemokines produced during liver senescence can attract further immune cells from the blood across the vascular endothelium and into liver tissue. In turn, this will be lead to an investigation of the potential of a novel therapeutic strategy developed by our group to prevent this inflammatory process. We hope this will suggest new ways to limit the development of bile duct senescence after liver transplantation.

Hypothesis
Induction of cholangiocyte senescence after liver transplantation promotes chemokine production leading to immune cell recruitment, further bile duct damage and eventual liver failure; blockade of chemokine function will inhibit this feedback process.

Project start date: September 2010

References
1. O'Boyle, G., Mellor, P., Kirby, J.A., and Ali, S. 2009. Anti-inflammatory therapy by intravenous delivery of non-heparan sulfate-binding CXCL12. Faseb J.
2. Newton, P., O'Boyle, G., Jenkins, Y., Ali, S., and Kirby, J.A. 2009. T cell extravasation: demonstration of synergy between activation of CXCR3 and the T cell receptor. Mol Immunol In press.
3. Ali, S., O'Boyle, G., Tyler, J.R., Robertson, H., and Kirby, J.A. 2009. Therapy with non-glycosaminoglycan-binding mutant CCL7: a novel strategy to limit allograft inflammation. Am J Transplantation In press.
4. Rygiel, K.A., Robertson, H., Marshall, H.L., Pekalski, M., Zhao, L., Booth, T.A., Jones, D.E., Burt, A.D., and Kirby, J.A. 2008. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest 88:112-123.
5. Ali, S., Jenkins, Y., Kirkley, M., Dagkalis, A., Manivannan, A., Crane, I.J., and Kirby, J.A. 2008. Leukocyte extravasation: an immunoregulatory role for alpha-L-fucosidase? J Immunol 181:2407-2413.
6. Ali, S., Robertson, H., Wain, J.H., Isaacs, J.D., Malik, G., and Kirby, J.A. 2005. A non-glycosaminoglycan-binding variant of CC chemokine ligand 7 (monocyte chemoattractant protein-3) antagonizes chemokine-mediated inflammation. J Immunol 175:1257-1266.

Eligibility and Value of the Award
Depending on how you meet the MRC’s eligibility criteria, you may be entitled to a full or a partial award. A full award covers tuition fees and an annual stipend of £13,290 (2009/10). A partial award covers fees only.

Person Specification
You should have, or expect to achieve, a first-class or upper-second-class Honours degree, in a relevant subject.

How to Apply
The University's postgraduate application form must be completed; selecting ‘Master of Research/Doctor of Philosophy - Medical Sciences (Cellular Medicine)’as the programme of study and inserting the reference number ICM83. Only mandatory fields need to be completed (no personal statement required) and a CV, a covering letter must be attached. The covering letter must state the title of the studentship, quote the reference number ICM83 and state how your interests and experience relate to the project.

Closing date for applications: early application is advised as applications will only be considered until a suitable candidate is found.

Further Information
For more details, please contact Professor John Kirby, j.a.kirby@ncl.ac.uk, or Dr Simi Ali, simi.ali@ncl.ac.uk