Identify new drug targets for treating OA by inducing autophagy

PROJECT OVERVIEW

Drugs targeting biological drivers of aging face unique translational challenges. In this DPhil, a translational strategy targeting an age-associated disease will be leveraged to advance an immediately clinically relevant intervention.  A parallel focus on mechanisms implicated in biological aging, toward eventually targeting multiple morbidities will also be maintained.

Approximately 10% of UK adults experience clinical symptoms of osteoarthritis (OA). The costs of community and social services for 9 million OA patients in the UK¹ exceed £250 million each year, with additional economic costs estimated to be in the billions. Cases of OA have increased by 16% in the UK over the past 20 years, fueled largely by increases in lifespan. Prevalence of OA increases with age, and the NIHR estimates that by 2035 62.6% of over-65s will be affected by OA. There are currently no FDA- or EMA-approved disease-modifying osteoarthritis drugs; treatment focuses on pain management².

OA is characterised by cartilage degradation resulting from proteolytic degradation of the matrix complicated by loss of chondrocyte cellularity within the articular cartilage. Evidence implicates autophagy (the main cellular bulk degradation pathway, which itself experiences age-associated decline) in articular cartilage homeostasis^3-5. Autophagy has a protective effect in normal cartilage⁶; OA cartilage (human and murine model) has reduced autophagy levels. Targeting cellular homeostasis mediators such as autophagy is, thus, a rational therapeutic strategy for OA. We have identified a novel signalling pathway downstream of spermidine that signals specifically to autophagy⁷. We have already shown that this pathway has the potential to reverse T and B cell senescence^7,8. The overarching goal of this DPhil is to identify new drug targets for treating OA by inducing autophagy. We will build on outcomes of a prior two-phase study Targeting autophagy for the treatment of osteoarthritis. Phase I proposed a genome-wide pooled CRISPR screen to identify novel targets regulating expression of autophagy pathway in OA models. Phase II proposed a selective drug screen to identify compounds which increase autophagy pathway in OA models. Bioinformatics analyses will link mechanistic pathways of drugs identified (Phase II) with CRISPR-screen identified gene targets (Phase I) to both validate genetic basis of interventions and identify novel gene targets. Here, we will validate candidates for new drug targets.

KEYWORDS 

Osteoarthritis, autophagy, ageing, Drug screen 

Training

The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease and their treatment. Training will be provided in techniques including flow cytometry, histochemistry, confocal microscopy, RNAscope assays, drug screen design and in vitro cell cultures (2D and 3D) of human chondrocytes, fibroblasts, various cell lines as well as using preclinical in vivo models of OA.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome.  Students will also be required to attend regular seminars within the Department and those relevant in the wider University.

Students will be expected to present data regularly in Departmental seminars, Alsaleh’s group, in supervisory research meetings’ and attend external conferences to present their research globally, with limited financial support from the Department.

Students will also have the opportunity to work closely with colleagues in The Centre for Osteoarthritis Pathogenesis Versus Arthritis (OA Centre) and Dr. Daniel Ebner’s group (Screening Facility). Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

KEY PUBLICATIONS 

1          Swain, S. et al. Trends in incidence and prevalence of osteoarthritis in the United Kingdom: findings from the Clinical Practice Research Datalink (CPRD). Osteoarthritis Cartilage 28, 792-801, doi:10.1016/j.joca.2020.03.004 (2020).

2          Cai, X. et al. New Trends in Pharmacological Treatments for Osteoarthritis. Front Pharmacol 12, 645842, doi:10.3389/fphar.2021.645842 (2021).

3          Lotz, M. K. & Carames, B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol 7, 579-587, doi:10.1038/nrrheum.2011.109 (2011).

4          Carames, B., Taniguchi, N., Otsuki, S., Blanco, F. J. & Lotz, M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum 62, 791-801, doi:10.1002/art.27305 (2010).

5          Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol 12, 412-420, doi:10.1038/nrrheum.2016.65 (2016).

6          Jeon, H. & Im, G. I. Autophagy in osteoarthritis. Connect Tissue Res 58, 497-508, doi:10.1080/03008207.2016.1240790 (2017).

7          Zhang, H. et al. Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. Mol Cell 76, 110-125 e119, doi:10.1016/j.molcel.2019.08.005 (2019).

8          Alsaleh, G. et al. Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. Elife 9, doi:10.7554/eLife.57950 (2020).

How to Apply

It is recommended that, in the first instance, you contact the relevant supervisor(s) and the Graduate Studies Office (graduate.studies@ndorms.ox.ac.uk), 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 in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the D.Phil will commence in October 2024.

Applications should be made to one of the following programmes using the specified course code.

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1) or

D.Phil in Musculoskeletal Sciences (course code: RD_ML2)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.