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Kennedy Trust Prize Studentships

  • Project No: KTPS-NC-14
  • Intake: 2021 KTPS-NC

PROJECT OUTLINE

Identification of new pain targets in osteoarthritis (OA) remains a high priority. Recent clinical trials demonstrate efficacy when nerve growth factor (NGF) is neutralised, and new treatments targeting NGF are likely to be approved by the FDA soon [2]. NGF is regulated in the joints of mice with OA at the time of spontaneous pain development (around 10 weeks after induction of disease) [3]. A number of cells within the joint are capable of making NGF but our studies suggest that a primary source is the cells of the damaged cartilage [1]. Another pain pathway that we have explored is that involving angiotensin II. Angiotensinogen, the precursor to angiotensin II, is also regulated in the joint at the same time as NGF and blockade of the angiotensin type II receptor (AT2) is strongly analgesic in murine OA. Published data from others suggests that NGF requires AT2 signalling to activate pain fibres (nociceptors). The precise relationship between angiotensin II signalling and NGF is unclear but they may act synergistically [5]. In this project, we would like to know whether both molecules are made by the same cells/tissues of the joint and whether their actions are dependent on one another. In addition, as these molecules are both found in the synovial fluid of patients with OA, we will address whether levels of ligand in OA joint fluid predict patient reported pain.

This project is a collaboration between groups in Oxford covering OA pathogenesis and neuroscience of pain. It will take advantage of established expertise in the molecular mechanisms underlying spontaneous pain behaviour in murine OA using validated surgical models and novel cutting-edge technologies, to address the following questions:

  • Which cells make NGF and angiotensin in painful murine OA? We have established RNAScope in murine knee joints which allows one to identify expression of specific single RNA molecules (NGF, angiotensinogen) in individual cells. We will use this to determine whether the cells of the cartilage are the principal drivers of NGF and angiotensin, or whether other tissues, such as the synovium and bone, are important in this regulation.
  • Are human nociceptors activated directly by NGF and angiotensin II and is this activation synergistic? We will use methodology described by Cader to derive nociceptors from human induced pluripotent stem cells (iPSCs) [4]. Using these cells, and established high throughput assays, we will assess the ability of NGF and angiotensin, either alone or in combination, and in the presence or absence of inhibitors, to activate nociceptors. We will also ask whether joint fluid from patients with osteoarthritis, from which NGF and angiotensin can be measured directly, is able to activate nociceptors.
  • · The STEpUP OA consortium (led by Vincent), is a large international consortium in which the joint fluid from 2000 patients with OA is undergoing proteomic profiling. We will examine whether levels in individual samples correlate with patient reported pain scores (already collected).

Thus, this project will improve our understanding of pain in OA, may identify novel treatment approaches, and will potentially identify ways of stratifying patients to improve treatment responses.

KEYWORDS

Osteoarthritis (OA), Pain, induced pluripotent stem cells (iPSC), nociceptor, nerve growth factor (NGF)

TRAINING OPPORTUNITIES

  • Induction of OA in mice by surgical joint destabilisation and measurement of pain behaviour over the following 20 weeks. Training by Zarebska.
  • RNAScope combined with immunohistochemistry of murine joint sections to visualise cells where NGF and angiotensin are regulated during the development of painful OA.
  • Derivation of nociceptors from human induced pluripotent stem cells (iPSCs) with validation of activation assays using recombinant NGF, angiotensin and human OA synovial fluid. 
  • Big data analysis using protein and pain measures to assess the correlation between molecular and clinical outcomes (with support from the STEpUP OA data analysis team).

KEY PUBLICATIONS

  1. Driscoll C, Chanalaris A, Knights C, Ismail H, Sacitharan PK, Gentry C, Bevan S, Vincent TL. Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic Mice Display Pain Behavior. Arthritis & rheumatology (Hoboken, NJ) 2016;68(4):857-867.
  2. Lane NE, Corr M. Osteoarthritis in 2016: Anti-NGF treatments for pain - two steps forward, one step back? Nature reviews Rheumatology 2017;13(2):76-78.
  3. McNamee KE, Burleigh A, Gompels LL, Feldmann M, Allen SJ, Williams RO, Dawbarn D, Vincent TL, Inglis JJ. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain 2010;149(2):386-392.
  4. Pettingill P, Weir GA, Wei T, Wu Y, Flower G, Lalic T, Handel A, Duggal G, Chintawar S, Cheung J, Arunasalam K, Couper E, Haupt LM, Griffiths LR, Bassett A, Cowley SA, Cader MZ. A causal role for TRESK loss of function in migraine mechanisms. Brain 2019;142(12):3852-3867.
  5. Vincent TL. Peripheral Pain Mechanisms in Osteoarthritis. Pain 2020; Vol 161:S138-S146.

THEMES

Neuroscience, Pain biology, Molecular pathogenesis of disease.

CONTACT INFORMATION OF ALL SUPERVISORS

Email

tonia.vincent@kennedy.ox.ac.uk

zameel.cader@ndcn.ox.ac.uk

Jadwiga.zarebska@kennedy.ox.ac.uk

KTRR SUPERVISION

Vincent has supervised 11 students to completion (100% success). In the past 5 years, 2 of these have been KTRR students (von Loga 2015, Kamalathevan 2018). Vincent will have one student remaining in October 2021.

 

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