The Bloomsbury Colleges | PhD Studentships | Studentships 2012 | Modulating NFkB signalling to target natural osteoarthritis in the STr/ort mouse
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Modulating Nfkb Signalling To Target Natural Osteoarthritis In The Str/Ort Mouse

Lead Supervisor: Andrew Pitsillides (Royal Veterinary College)

Co-Supervisors: Jose Prieto (The School of Pharmacy), Donald Palmer (Royal Veterinary College)

Osteoarthritis (OA) is a joint disease with major health and financial impact in humans and animals. OA is multifactorial and its aetiology and therapeutic targets remain elusive. STR/ort mice develop OA spontaneously with a natural progression resembling human OA. Our pilot microarray analyses have revealed that chondrocytes in young STR/ort mice exhibit a pronounced immune/ inflammatory gene signature centred firmly on nuclear factor-kappaB (NFkB) signalling. We have also found that STR/ort mice, prior to the onset of OA, have an enlarged spleen containing activated T and B-cells; displaying an immune phenotype also consistent with NFkB activation. This leads us to hypothesize that: the immune phenotype and OA in STR/ort mice share a common molecular aetiology reliant on NFkB signalling, which can be inhibited by cannabinoid receptor 2 agonists.

The student’s aims will be to:

  • Firstly, further define the immune-phenotype of STR/ort mice and use these data, together with recently mapped chondrocyte gene signature, to develop a predictive ‘mathematical’ model of OA.
  • Secondly, determine immune-phenotype and chondrocyte expression profile in response to acute NFkB inhibition and cannabinoid receptor 2 (CB2) agonist in STR/ort mice to inform our computational model, and
  • Finally, evaluate whether in the long-term such treatment modifies OA in STR/ort mice.

This project is truly multidisciplinary, bringing together complementary expertise at SoP in NFkB signalling and mathematical modelling (JP) and the RVC in immunology and ageing (DP) and osteoarthritis research (AAP). This collaboration allows the transfer of material, knowledge and technology to take place; thereby enhancing the impact of this proposal. In fact, this specific project is the first to begin to close the loop with AP’s second themed research endeavour in the developmental biology of joint formation, which is now beginning to culminate (see recent review; Pitsillides AA and Beier F. (2011) Cartilage biology in osteoarthritis – lessons from developmental biology. Nature Reviews Rheumatology. 7(11), 654-663).

This projects falls within the remits of the RVC and SoP, as well as with BBSRC and will lead to future larger scale collaboration.The student will participate in Ph.D. training programmes operating at both institutes. At the RVC, the student will undertake a statistics course, induction in laboratory safety, IT skills, be trained as an undergraduate tutor, and have the opportunity to supervise an undergraduate laboratory project. The student will be participating in lab meetings involving to journal clubs and presenting data at both institutes. The student will also have the opportunity to present their data at Departmental seminars and in Immunology and Skeletal Biology group meeting at the RVC. At the SoP, the student will receive expert training in mathematical modelling and principals of pharmacology; while at the RVC, this will include flow cytometry, cell culture, PCR, animal handling and a broad understanding of the Osteoarthritis and Cartilage research environments. These two unique research environments will provide the student with a far broader perspective and transform the student into a truly interdisciplinary scientist

Key References:

Pitsillides AA and Beier F. (2011) Cartilage biology in osteoarthritis: lessons from developmental biology. Nature Reviews Rheumatology. 7(11):654-63.

Cortes-Cabrera A & Prieto JM. (2010) Food Chemistry 118:141–46.

Poulet B, Hamilton RW, Shefelbine S and Pitsillides AA. (2011) Characterising a novel and adjustable non-invasive murine knee joint loading model. Arthritis & Rheumatism. 2011 63(1):137-47.

Further details about the project may be obtained from:

Andrew Pitsillides, apitsill@rvc.ac.uk, http://www.rvc.ac.uk/Staff/apitsillides.cfm

Further information about PhDs at the Royal Veterinary College is available from:

http://www.rvc.ac.uk/Postgraduate/Research/Index.cfm

Application forms and details about how to apply are available from:

http://www.rvc.ac.uk/Postgraduate/Info/HowToApply.cfm#research

Graduate School, Royal Veterinary College, Royal College Street, London, NW1 0TU

+44 (0)20 7468 5134

Post Graduate Admissions Officer, Mr John Mackenzie, graduateschool@rvc.ac.uk, +44 (0)20 7468 5134

Applications must include:

  • a CV
  • a personal statement explaining why you would like to undertake this particular project
  • a copy of your degree certificate(s)
  • a transcript of your degree(s) - this must be a certified translation if the original was not issued in English
  • 2 confidential references
  • Overseas students must also provide evidence that they have met the College's English language requirement though this may be submitted later.

This studentship is now closed.