Kennedy Trust Prize Studentships
Does angiotensin signaling control NGF-mediated pain in osteoarthritis?
Background and preliminary data
Pain in osteoarthritis (OA) is the most important clinical symptom in disease and poses a massive societal burden. We are one of the only groups worldwide who measures spontaneous painful behavior in mice with OA , . In 2010 we published that nerve growth factor (NGF) is regulated in the joints of mice at precisely the time at which they develop spontaneous pain-related behavior. This study also showed that targeting NGF was analgesic in these animals. The same year the first clinical studies using antibodies against NGF were published . These also demonstrated high efficacy of NGF targeting in OA pain. There is a high expectation that the FDA will approve this class of drugs for human OA pain within the next 12 months.
In parallel we have been studying the effects of targeting the angiotensin II type 2 receptor (AT2) in experimental OA pain. AT2 receptors are found on pain fibres and have recently been shown to be novel analgesics in neuropathic pain . In the course of these preliminary studies we have shown that (i) blocking AT2 is an effective analgesia in mice with OA pain (ii) angiotensinogen (the precursor of angiotensin II, the ligand for AT2) is up-regulated in the joints of mice at the time pain develops and is co-regulated with NGF. This raises some important questions that will be addressed in this project:
- Is NGF regulated by angiotensinogen and/or angiotensin in the joint?
Does targeting AT2 suppress NGF induction in OA?
- Does tissue injury directly drive angiotensinogen production in the joint, and which tissues are regulating it?
- Do levels of angiotensin or NGF in the synovial fluid of patients relate to clinical symptoms and could this act as a stratifier for treatment (through recently funded STEpUP OA consortium)?
In vivo models of OA induced by surgical joint destabilization; measurements of painful behavior by incapacitance testing; tissue microdissection and RNA extraction; RT-PCR; microarray analysis; tissue injury assays; confocal microscopy; handling human diseased and normal tissue; Good Clinical Practice (GCP) training; large data analysis.
Vincent: Director of OA Pathogenesis Centre. Currently has 4 students, 2 post docs and 1 technician working in her team. She also manages another 4 technicians associated with the OA Centre (most of whom are post-doctoral scientists). Wattis the Translational OA lead within the Centre. The group works closely with other PIs within the OA Centre. For further information: https://oacentre.kennedy.ox.ac.uk
or contact Tonia Vincent directly at firstname.lastname@example.org
- J. J. Inglis, K. E. McNamee, S.-L. Chia, D. Essex, M. Feldmann, R. O. Williams, S. P. Hunt, and T. Vincent, “Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system.,” Arthritis Rheum., vol. 58, no. 10, pp. 3110–3119, Oct. 2008.
- C. Driscoll, A. Chanalaris, C. Knights, H. Ismail, P. K. Sacitharan, C. Gentry, S. Bevan, and T. L. Vincent, “Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic Mice Display Pain Behavior.,” Arthritis Rheumatol, vol. 68, no. 4, pp. 857–867, Apr. 2016.
- K. E. McNamee, A. Burleigh, L. L. Gompels, M. Feldmann, S. J. Allen, R. O. Williams, D. Dawbarn, T. L. Vincent, and J. J. Inglis, “Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain,” Pain, vol. 149, no. 2, pp. 386–392, May 2010.
- N. E. Lane, T. J. Schnitzer, C. A. Birbara, M. Mokhtarani, D. L. Shelton, M. D. Smith, and M. T. Brown, “Tanezumab for the Treatment of Pain from Osteoarthritis of the Knee,” N. Engl. J. Med., vol. 363, no. 16, pp. 1521–1531, Oct. 2010.
- A. S. C. Rice, R. H. Dworkin, T. D. McCarthy, P. Anand, C. Bountra, P. I. McCloud, J. Hill, G. Cutter, G. Kitson, N. Desem, M. Raff, EMA401-003 study group, “EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial.,” Lancet, vol. 383, no. 9929, pp. 1637–1647, May 2014.
Translational Medicine; Tissue Remodelling and Regeneration
HOW TO APPLY
The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Directors of Graduate Studies who will be able to advise you of the essential requirements.
Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system.
The application guide and form is found online and the DPhil or MSc by research will commence in October 2019.
When completing the online application, please read the University Guide.