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(WIS) Understanding the molecular basis of cartilage lubrication – an essential aspect of articular joint function: biophysical approaches to investigate supramolecular synergy

  • Full or part time
  • Application Deadline
    Thursday, February 28, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Articular cartilage, which coats the ends of bones in joints such as hips and knees, is a uniquely well-lubricated tissue. No synthetic material can match the almost frictionless movement between the cartilage surfaces as they slide past each other during joint articulation. This is crucial for the maintenance of healthy joints and the prevention of joint diseases. For example, in osteoarthritis, loss of effective lubrication contributes to progressive cartilage damage and, ultimately, exposure of underlying bone. However, the molecular basis of cartilage lubrication is poorly understood. This project is aimed at elucidating this remarkable mechanism, through a combination of biochemical and biophysical approaches. Recent research by Jacob Klein’s group at the Weizmann Institute of Science (WIS), Israel, in collaboration with Tony Day in Manchester, has identified that the polysaccharide hyaluronan, a major component of cartilage and synovial fluid, likely synergises with proteoglycans and phospholipids to generate a boundary lubrication layer on the cartilage surface. This project will extend these findings to determine the molecular basis of how such macromolecular complexes generate these lubricating properties and identify how they are altered during joint disease. The research will utilise state-of-the-art biophysical methodologies available at the University of Manchester (years 1 and 4) and WIS (years 2 and 3), where the student will become expert in a wide range of techniques, including the use of surface force balances (SFBs) and isothermal titration calorimetry. This will provide important information on the stoichiometries and thermodynamics of the molecular interactions and the frictional properties of supramolecular complexes of hyaluronan with proteins/proteoglycans and phosopholipids at the sub-nanometre level. The resulting data will be combined to inform theoretical models, where the hypotheses generated will be tested by further experimentation. The student will also gain expertise in biochemical techniques, such as recombinant protein production and glycobiology. This multidisciplinary project will provide an excellent training for individuals considering careers in academia or industry.

The project will be supervised Tony Day and Caroline Milner (University of Manchester, UK) and by Jacob Klein (WIS, Israel). Professor Klein is an expert on polymer physics and a pioneer of SFB technologies to investigate the friction and lubrication of biological systems; Professor Day and Dr Milner are experts on hyaluronan-protein interactions, e.g. in the context of physiological and disease processes, and are working together to develop a protein-based biological for osteoarthritis.

Entry Requirements
Applicants must be from the UK/EU and have obtained (or be about to obtain) a minimum 2:1 Bachelors honours degree or equivalent in a relevant subject area.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Weizmann Institute of Science, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Chen, M., Briscoe, W.H., Armes, S.P. & Klein, J. Lubrication at physiological pressures by polyzwitterionic brushes. (2009) Science 323: 1698-1702.

Seror et al., Day, A.J., Maroudas, A. & Klein, J. (2011) Articular cartilage proteoglycans as boundary lubricants: structure and frictional interaction of surface-attached hyaluronan-aggrecan complexes. Biomacromolecules J. 12: 3432-3443.

Seror et al., Day, A.J. & Klein J. Supramolecular synergy in the boundary lubrication of synovial joints. (2015) Nature Communications 6: 6497 DOI: 10.1038/ncomms7497.

Briggs et al., Milner, C.M. & Day, A.J. (2015) Metal ion-dependent heavy chain transfer activity of TSG-6 mediates assembly of the cumulus-oocyte matrix. J. Biol. Chem. 290: 28708-28723.

Jahn, S., Seror, J. & Klein, J. Lubrication of articular cartilage. (2016) Annu. Rev. Biomed. Eng. 18: 235-258.

Day, A.J. & Milner, C.M. TSG-6: a multifunctional protein with anti-inflammatory and tissue-protective properties. Matrix Biology, in press. doi: 10.1016/j.matbio.2018.01.011.

Lin et al., & Klein, J. Lipid-hyaluronan synergy strongly reduces intrasynovial tissue boundary friction. (2019) Acta Biomaterialia 83, 314–321.

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