About the Project
Parasitic worms (helminths) infect most mammals including a third of the human population. Although rarely causing death, these parasites cause significant morbidity in part by the damage they inflict while migrating through the tissues. In response to helminths, mammals mount a strong type 2 immune response that contributes both to parasite killing and repair of damaged tissue. It is becoming increasingly appreciated that Type 2 immunity is not just involved in the response to helminth infection but contributes to tissue repair and extracellular matrix deposition even during sterile injury, contributing to fibrotic diseases such as asthma, cardiovascular disease and liver fibrosis. Among the most abundant proteins produced during a type 2 immune response and strongly associated with fibrosis are the chitinase like proteins (CLPs). Despite their abundance in a vast range of pathological conditions, their specific functions are not known. They appear to promote an inflammatory response that helps control helminth infection, but at the cost of further tissue damage. However, they also promote the subsequent repair response and recent unpublished data from the Allen lab has demonstrated that CLPs contribute directly to tissue repair. How CLPs perform these diverse functions is entirely unknown. What is known is that CLPs bind to the heparan sulphate (HS) chains of proteoglycans (PGs). HSPGs are found in all mammalian tissues (i.e. on cell surfaces and in the extracellular matrix). HSPGs mediate diverse functions, including regulating both innate and adaptive immunity (e.g. through binding to chemokines, complement components and growth factors). While evidence exists that human and murine CLPs interact with heparin (a highly sulphated form of HS), the specificity of this interaction has not been investigated nor is it known whether CLPs bind to other glycosaminoglycans (GAGs). The aim of this project is therefore to interrogate the binding properties of mammalian CLPs to GAGs in order to unravel the function of the CLPs at the biochemical and tissue level. The project brings together supervisors with expertise in GAGs and biochemistry (Tony Day) and expertise in CLPs and immunology (Judi Allen). Under their joint supervision, the student will ask: Are GAGs the physiologically relevant binding partners of CLPs? Where do CLPs bind in tissues and do GAGs act as postal codes that determine local CLP function? The answers to these questions will generate new hypotheses, which will then be tested in mouse models of parasite infection and tissue repair.
Day: http://www.wellcome-matrix.org/research_groups/tony-day.html
Allen: http://www.manchester.ac.uk/research/judi.allen
Funding Notes
This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
Sutherland, T.E., Logan, N., Rückerl, D., Humbles, A.A., Stockinger, B., Maizels, R. M. & Allen, J.E. (2014) Chitinase-like proteins promote IL-17-mediated neutrophilia in a trade-off between nematode killing and host damage. Nature Immunology 15: 1116-25
Allen, J.E. & Sutherland, T.E. (2014) Host protective roles of type 2 immunity: parasite killing and tissue repair, flip sides of the same coin. Seminars in Immunology 26: 329-40
Gause, W.C., Wynn, T.A. & Allen, J.E. (2013). Type 2-immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nature Reviews Immunology 13: 607-14
Dyer, D.P., Salanga, C.L., Johns, S.C., Valdambrini, E., Fuster, M.L., Milner, C.M., Day, A.J. & Handel, T.M. (2016) The anti-inflammatory protein TSG-6 regulates chemokine function by inhibiting chemokine-glycosaminoglycan interactions. J. Biol. Chem. 291: 12627-40
Clark, S.J., Bishop, P.N. & Day, A.J. (2013) The proteoglycan glycomatrix: a sugar microenvironment essential for complement regulation. Frontiers in Immunology 4: 412 doi: 10.3389/fimmu.2013.00412