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(MRC DTP) Immunological consequences of the loss of marrow niche homeostasis in ageing and disease

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  • Full or part time
    Dr Swift
    Dr Grainger
    Dr Richardson
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Maintenance of the marrow niche is essential to the viability of haematopoietic stem cells (HSCs), the progenitors for all immune cell populations. The niche contains HSCs and mesenchymal stromal cells (MSCs), which interact with each other, as well as with soluble and matrix-associated factors in an environment with diverse mechanical properties. MSCs play a vital role in HSC maintenance through the expression of soluble factors [1], but how this complex homeostatic process is affected by ageing remains poorly understood [2].

During ageing the mechanical environment of the marrow changes, in part through increased production of adipose tissue [3], as well as changes in the physical loads experienced by ageing bones [4]. MSCs respond to mechanical inputs, for example in determining cell fate [5], but the effect of a changing mechanical environment on the ability of MSCs to support and maintain HSCs is not known. Both HSCs and MSCs exist in dynamic, heterogeneous populations with varied functional characteristics.

This project will generate a detailed profile of HSC/MSC niche interactions and characterize how they are altered in ageing and disease. Data will be collected from high-content imaging, mass spectrometry proteomics and flow cytometry (e.g. CyTOF mass cytometry – using conjugated heavy metals to quantify large numbers of proteins on a single cell level), and will examine (i) cellular responses to mechanical inputs; (ii) responses to biochemical factors (known soluble factors and conditioned media) and (iii) whether responses are influenced by replicative-induced senescence (used as an in vitro model of ageing).

http://www.wellcome-matrix.org/research_groups/joe-swift.html

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. 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 our website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mrc-dtp/.

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

1. Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010, 466, 829-U859
2. Geiger, H.; de Haan, G.; Florian, M.C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immun. 2013, 13, 376-389
3. Justesen, J. et al. Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology 2001, 2, 165-171
4. Gurkan, U.A.; Akkus, O. The mechanical environment of bone marrow: A review. Ann. Biomed. Eng. 2008, 36, 1978-1991
5. Engler, A.J. et al. Matrix elasticity directs stem cell lineage specification Cell 2006, 126, 677-689

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