Advancing Drug Delivery for Regeneration and Repair of the Aging Cartilage (Botnar-2026-01)

About the project

About the Project 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. 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 UK 1 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 management 2 . OA is characterized by cartilage degradation resulting from proteolytic degradation of the matrix complicated by loss of chondrocyte cellularity within the articular cartilage. Evidence supports the role of 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 cartilage 6 ; OA cartilage (in human and murine models) has shown 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 autophagy 7 . 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 and validate novel therapeutic targets for osteoarthritis by restoring autophagy and cellular homeostasis. Building on a previous two-phase programme that combined genome-wide CRISPR screening with targeted drug discovery to identify regulators and pharmacological activators of autophagy in OA models, this project will focus on mechanistic validation and translational development of the most promising candidates. To accelerate translation towards human-relevant preclinical models, candidate pathways will be evaluated in advanced patient-derived three-dimensional musculoskeletal models incorporating microfluidic technologies and physiologically relevant mechanical loading. This integrated approach will enable assessment of drug efficacy within a biomimetic joint environment, while providing mechanistic insight into autophagy-mediated cartilage protection and repair. Supervisors: Dr Ghada Alsaleh: https://www.ndorms.ox.ac.uk/research/research-groups/alsaleh-group-aging-in-the-musculoskeletal-system . Associate Professor Dario Carugo: https://www.ndorms.ox.ac.uk/team/dario-carugo . Associate Professor Pierre-Alexis Mouthuy: https://www.materials.ox.ac.uk/peoplepages/mouthuy.html KEYWORDS: Osteoarthritis, autophagy, ageing, Drug screen. Training The Botnar Research Centre hosts the University of Oxford's Institute of Musculoskeletal Sciences, providing an outstanding multidisciplinary environment for research into musculoskeletal disease and regenerative medicine. The student will receive comprehensive training in musculoskeletal biology, ageing research, drug discovery, and advanced bioengineering approaches. Experimental training will include flow cytometry, histochemistry, confocal microscopy, RNAscope, high-content drug screening, 2D and 3D cell culture, patient-derived organoid models, nanotechnologies for drug development and screening, and preclinical models of osteoarthritis. In addition, the student will receive specialist training in tissue engineering, and quantitative image analysis, providing expertise in developing physiologically relevant human joint models for therapeutic testing. 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. The multidisciplinary supervisory team will provide complementary expertise spanning musculoskeletal ageing, autophagy biology, tissue engineering and translational bioengineering. This interdisciplinary training will equip the student with a unique combination of biological, engineering and translational skills that are highly relevant to the development of next-generation therapies for osteoarthritis. Students will be expected to present data regularly in Departmental seminars, the Alsaleh’s group and to attend external conferences to present their research globally. Students will also have the opportunity to work closely with the Centre for Osteoarthritis Pathogenesis Versus Arthritis (OA Centre, https://www.kennedy.ox.ac.uk/oacentre/oacentre ). 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). How to Apply Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team ( graduate.studies@ndorms.ox.ac.uk ), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application. 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 DPhil or MSc by research will commence in October 2027. Applications should be made to one of the following programmes using the specified course code. Please include the appropriate programme title(s) on your advertisement. D.Phil in Musculoskeletal Sciences (course code: RDML2) D.Phil in Molecular and Cellular Medicine (course code: RDMP1) For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford . Applications open mid-September Application deadline: 12:00 on 1st December

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