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Targeting Notch signaling to treat osteoarthritis pain. (#202012)

About This PhD Project

Project Description

Pain is the principal problem for thousands of individuals who suffer from osteoarthritis (OA), the most common form of joint disease. Our understanding of the mechanisms that drive painful disease have come from recent detailed molecular studies in mouse models of OA[1] [2] as well as clinical trials [3]. Collectively these studies have identified nerve growth factor (NGF) as a key driver. Indeed, neutralising antibodies to NGF are highly effective analgesics in OA patients and may soon be granted a licence by the FDA.

NGF is known to promote pain sensitisation, sprouting of pain fibres and new pain fibre formation. It has been implicated in the abnormal innervation of the articular cartilage in human disease and is regulated in the articular cartilage of OA mice when spontaneous pain behaviour develops for the first time [1].

New nerve formation requires the formation of blood vessels that support their survival. Notch signalling is a key regulator of physiological and pathophysiological angiogenesis. New blood vessels form by a carefully orchestrated process that involves Notch signalling. In the skeletal system, Notch promotes blood vessel growth and bone formation. Thus, newly forming blood vessels are vulnerable and can be targeted by blocking Notch. We hypothesise that inhibiting Notch specifically in endothelial cells will cause regression of new blood vessels leading to a failure to support pain fibre formation, thus reducing pain. Specifically, we will address the following questions:
(i) What is the time course over which new nerves/blood vessels form after OA has been induced and how does this correlate with pain behaviour in mice? OA will be induced by partial meniscectomy. Ex vivo imaging will be performed using high-resolution laser scanning microscopy through the depth of the tissue using immunohistochemistry or by transgenic reporters. Both methodologies have been developed and validated by Kusumbe[4], [5].
(ii) Which are the cells of the damaged joint that are making NGF? This will be addressed by RNAScope, recently set up in murine joints in the Vincent lab.
(iii) Does deletion of Notch specifically in endothelial cells prevent the formation of new nerves and pain when deleted early in OA or cause regression of nerves and reduction in pain if deleted once pain is established? Endothelial Notch will be deleted by crossing a Cre recombinase that is expressed only in endothelial cells with the floxed Notch allele. It will be induced in a time-controlled fashion by injection of tamoxifen.
(iv) Does endothelial-specific deletion of Notch impact osteophyte formation? How does this impact pain in OA.?

The individual will work between the Vincent group (In vivo OA pathogenesis, pain behaviour) and Kusumbe (in vivo vascular biology) using state of the art technologies to address this important and clinically relevant area. The individual will be part of the Centre for OA Pathogenesis based at the Kennedy Institute; a group of around 40 individuals working on basic and clinical aspects of OA.

Training Opportunities

In vivo OA pathogenesis; surgical induction, pain behavior measurements.
Generation of conditional knockout and use of transgenic reporter mice.
Confocal microscopy; using state of the art microscopy to acquire 3D images of blood vessels in joint, RNAScope.

Key Publications

[1] 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.

[2] I. S. von Loga, A. El-Turabi, L. Jostins, J. Miotla-Zarebska, J. Mackay-Alderson, A. Zeltins, I. Parisi, M. F. Bachmann, and T. L. Vincent, “Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis.,” Ann. Rheum. Dis., pp. annrheumdis–2018–214489, Mar. 2019.

[3] N. E. Lane and M. Corr, “Osteoarthritis in 2016: Anti-NGF treatments for pain - two steps forward, one step back?,” Nat Rev Rheumatol, vol. 13, no. 2, pp. 76–78, Jan. 2017.

[4] A. P. Kusumbe, S. K. Ramasamy, T. Itkin, M. A. Mäe, U. H. Langen, C. Betsholtz, T. Lapidot, and R. H. Adams, “Age-dependent modulation of vascular niches for haematopoietic stem cells.,” Nature, vol. 532, no. 7599, pp. 380–384, Apr. 2016.

[5] S. K. Ramasamy, A. P. Kusumbe, L. Wang, and R. H. Adams, “Endothelial Notch activity promotes angiogenesis and osteogenesis in bone.,” Nature, vol. 507, no. 7492, pp. 376–380, Mar. 2014.

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