Targeting autophagy for the treatment of osteoarthritis (NDORMS 2023/1)

Population ageing is one of the most significant social transformations of this century and impacts different sectors of society including labour force and financial resources. Although the increase in life span is one of the greatest achievements of humanity, age-related diseases, such as osteoarthritis (OA), limit health span. Therefore, studies in this field are needed to identify new strategies to treat or prevent these age-related diseases. Ageing research has made significant progress over recent years, giving us several candidate molecules and processes that are generally considered to contribute to the ageing process and together determine the ageing phenotype.

The process of cellular senescence contributes to age-related dysfunction and chronic inflammation. Accumulating evidence indicates that cartilage degradation, which is the main feature of OA, is due to cellular senescence. We recently revealed the role of autophagy, the main cellular bulk degradation pathway, in immune senescence. Interestingly, inducing autophagy in a mouse model of OA decreases disease burden. Our data indicate that autophagy levels decrease with age in human peripheral blood mononuclear cells, and autophagy levels can be increased by spermidine to reverse the ageing phenotype of these cells. In this project we will study the impact of autophagy on cellular senescence of joint tissues in OA mice models and from OA patients, and how this pathway contributes to OA pathogenesis. The ultimate aim of this work is to harness autophagy as a drug target by using state-of-the-art techniques to assess autopgahy expression and specific age-related phenotypes in the joint tissue in OA mice models and from OA patients.

KEYWORDS: Osteoarthritis, autophagy, ageing, Drug screen. Ageing, Arthritis, Immunology.

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 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,  https://www.kennedy.ox.ac.uk/oacentre/oacentre), Oxford, DRFZ Institute ( https://www.drfz.de/uber-uns/koepfe/prof-dr-max-loehning/), Berlin, TIGEM Institute ( https://www.tigem.it/research/faculty/settembre), Naples, and The

Buck Institute for ageing research (https://www.buckinstitute.org/lab/campisi-lab/), California.

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 (Nuffield Department of Orthopaedics) and run by the IT department (information will be provided once accepted to the programmer).

Supervisors: 

Dr Ghada Alsaleh: https://www.ndorms.ox.ac.uk/research/research-groups/alsaleh-group-aging-in-the-musculoskeletal-system.

Professor Christopher Buckley: https://www.ndorms.ox.ac.uk/research/research-groups/stromal-cell-biology.

Associate Professor Sarah Snelling: https://www.ndorms.ox.ac.uk/research/research-groups/snelling. 

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 Graduate Studies Office ([Email Address Removed]) 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 DPhil will commence in October 2023.

Applications should be made to one of the following programmers 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.

CONTACT INFORMATION:

Dr Ghada ALSALEH

Email: [Email Address Removed]