PhD Studentship: Does metabolic perturbation mediate the inflammatory phenotype of the obese OA syn

Location
United Kingdom
Posted
Jan 10, 2018
Closes
Feb 16, 2018
Organization Type
University and College
Hours
Full Time
Details

Research interests/description of main research theme:

Osteoarthritis (OA) is a painful joint condition and a leading cause of disability in the world. Unfortunately there is currently no cure for the disease, and there are limited treatment options. Importantly, despite historically being seen as a “wear and tear” disease of the cartilage there is now evidence that inflammation of the synovial joint lining (synovitis) plays a key role to the disease pathology (1, 2). Therefore, understanding how synovitis in the OA joint is regulated may lead to the development of new therapeutics.

Importantly, we have found that synovitis is pronounced in obese OA patients, with elevated levels of pro-inflammatory cytokines in the synovial fluid. Critically, our research has attributed this obesity-associated synovitis to the phenotype of the obese synovial fibroblast which secretes greater pro-inflammatory cytokines(3) and exhibits differential expression of inflammatory mRNAs and inflammation-associated non-coding RNAs including lncRNAs and snoRNAs(4, 5). These differences in OA pathology suggest that lean and obese OA patients might benefit from different treatment strategies.

In attempting to identify candidate cellular drivers of this inflammatory synovial fibroblast phenotype it has recently become clear that inflammatory processes are metabolically demanding(6). Indeed, we have found that the metabolic profile of the synovial fibroblast correlates with the secretion of pro-inflammatory IL-6. We hypothesise therefore that the synovial joint inflammation seen in obese OA patients is underpinned by therapeutically targetable metabolic deviation. The overarching objective of this studentship is thus to investigate the relationship between cellular bioenergetics (metabolism) and the inflammatory phenotype of the OA synovial fibroblast.

The project will be conducted within the MRC-ARUK Centre for Musculoskeletal Ageing Research. The Centre has state-of-the-art molecular and cellular biology laboratories and strong collaborative links with NHS colleagues including a partnership with the Royal Orthopaedic Hospital. We are therefore ideally positioned for access to clinical OA patient samples and to the conduct all the techniques required for this translational project. This research environment will provide excellent training and development for anyone who wishes to pursue a research career in the area of ageing and inflammatory disease, with exposure to both clinicians and basic research scientists. The successful candidate will predominantly work under the supervision of Dr Simon Jones and Dr Jane Falconer (University of Birmingham) and will receive training in a diverse range of techniques including Bioinformatics, primary cell culture, qRTPCR and RNA sequencing analysis. In addition, the student will undertake studies in the laboratory of Dr Lisa Chakrabarti (University of Nottingham) to assess cellular mitochondrial function and will undertake a secondment of up to 3 months to work in the laboratory of Dr Mandy Peffers (CIMA, University of Liverpool) to conduct proteomic and snoRNA expression analysis.

 

Person Specification

Applicants should have a strong background in biological sciences, and ideally a background in molecular and cellular biology. They should have a commitment to research in ageing and age-related inflammatory disease and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

 

How to apply

Informal enquiries should be directed to Dr Simon Wyn Jones (S.W.Jones@bham.ac.uk)

 

Funding Notes

3-year funded studentship through the MRC-ARUK Centre for Musculoskeletal Ageing Research (CMAR). Students should have home or EU status: and have been 'ordinarily resident' in the UK for 3 years prior to the start of the studentship to be eligible for the full award (tuition fees, research support costs, and a tax-free stipend at the Research Council rate). Applicants who have been 'ordinarily resident' in another EU member state may be eligible for a fees only award. Please see RCUK terms and conditions for further information.

This studentship is full-time and will begin on 1st of October 2018

 

References

  1. Philp AM, Davis ET, Jones SW. Developing anti-inflammatory therapeutics for patients with osteoarthritis. Rheumatology (Oxford). 2017 Jun 1;56(6):869-881.
  2. Tonge DP, Pearson MJ, Jones SW. The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics. Osteoarthritis Cartilage. 2014 May;22(5):609-21.
  3. Pearson MJ, Herndler-Brandstetter D, Tariq M, Nicholson T, Philp AM, Davis ET, Jones SW*, Lord JM*. IL-6 secretion in osteoarthritis patients is mediated by chondrocyte-synovial fibroblast cross-talk and is enhanced by obesity. May 2017 Scientific Reports
  4. Pearson MJ, Philp AM, Heward JA, Roux BT, Walsh DA, Davis ET, Lindsay MA, Jones SW. Long Intergenic Noncoding RNAs Mediate the Human Chondrocyte Inflammatory Response and Are Differentially Expressed in Osteoarthritis Cartilage. Arthritis Rheumatol. 68(4):845-56 (2016).
  5. Pearson MJ, Jones SW. Long Noncoding RNAs in the Regulation of Inflammatory Pathways in Rheumatoid Arthritis and Osteoarthritis. Arthritis Rheumatol. 68(11):2575-2583 (2016).
  6. Falconer J. Marshall JL, Raizada S, Adams H, Philp A, Filer A, Raza K, Young SP, Buckley CD. Synovial fibroblasts display metabolic memory and bioenergetic reprogramming during the transition from resolving to persistent disease. Under review, Arthritis and Rheumatology.