Exploring Stem Cell Regulation by Heparan Sulphates using Chemical Biology and Glycomics Strategies

Description

Heparan sulphates (HS) are complex sulphated polysaccharides expressed at the cell surface. They are essential co-receptors for many proteins, most notably many signalling growth factors, and they act as dynamic regulators of protein function. Studies on these sugars are at the forefront of the glycobiology field and will be a critical facet of the post-genomic era; “glycomics” (large scale analysis of sugar structure and function) is increasingly important in partnership with proteomics for understanding complex cellular functions. We are actively studying the structure-activity relationships of HS in relation to cell signalling, development and disease, in particular using novel chemically synthesized HS compounds (see references below).

In addition, we have recently discovered that HS saccharides can differentially regulate differentiation of embryonic stem cells, and can modulate the phenotype of breast cancer stem cells (including their chemo-sensitivity); the underlying mechanisms involve simultaneous manipulation of multiple signaling pathways (Baty, Alghamdi & Turnbull, manuscripts in preparation).

This PhD project will focus on methods for purification and analysis of HS structures from stem cells (to assess changes with phenotypic switches), and further exploitation of synthetic HS saccharides to investigate mechanisms of selective control of stem cell phenotypes. These techniques will allow dissection of the structure-function relationships of HS in stem cell regulation and may ultimately lead to anti-cancer treatments, and new regenerative medicine applications.

Specific practical training:
1. Glycobiology (glycan purification; cell culture; bioassays; glycobioarrays)
2. Glycoanalysis (HPLC/FPLC; glycan analysis; ES mass spec sequencing)
3. Glycomics (large scale glycoanalysis; saccharide microarrays; glycobioarrays)

Generic skills training:

  • Regular oral presentations of work at group meetings and producing reports 
  • Attend national and international meetings and present results (poster/short talk) 
  • Lab exchanges with collaborators (UK/overseas). 


The project is suited to a student with at least a good B.Sc. Upper Second in Biological or Life Sciences.

Please note this position will remain open until a suitable candidate is found. Early applications are encouraged. 

To apply please click here

Availability

Open to students worldwide

Funding information

Self-funded project

The project is open to both European/UK and International students. It is UNFUNDED and applicants are encouraged to contact the Principal Supervisor directly to discuss their application and the project.

Assistance will be given to applications who are applying to international funding schemes.

The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs of typically £9500 per year.

A fee bursary may be available for well qualified and motivated applicants.

Details of costs can be found on the University website.

Supervisors

References

C Duckworth, SE Guimond, Hughes A, French, N; Yates, EA; J Rhodes, M Pritchard, L Yu & JE Turnbull. (2015) Chemically modified, non-anticoagulant heparin derivatives are potent galectin-3 binding inhibitors and inhibit circulating galectin-3-mediated metastasis. Oncotarget 6, 23671-87

R Schwörer, OV. Zubkova, JE. Turnbull and PC. Tyler. (2013) Synthesis of a Targeted Library of Heparan Sulfate Saccharides as Inhibitors of -Secretase: Potential Therapeutics for Alzheimer’s Disease. Chemistry European Journal. 19, 6817-23.

JR Higginson, SM Thompson*, A Santos-Silva, SE Guimond, JE Turnbull and SC Barnett. (2012) Differential Sulfation Remodelling of Heparan Sulfate by Extracellular 6-O-sulfatases Regulates Fibroblast Growth Factor-induced Boundary Formation By Glial Cells: Implications for Glial Cell Transplantation Journal of Neuroscience 32, 15902-15912

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