Targeting TFEB for the treatment of Osteoarthritis
- Project No: NDORMS 2022/1
- Intake: 2022
Population ageing is becoming one of the most significant social transformations of this century which 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 diseases. Ageing research has made significant progress over recent years, giving us several candidate hallmarks 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 the transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, the main cellular bulk degradation pathway, in immune senescence (Zhang, Alsaleh et al. 2019). Interestingly, TFEB overexpression in a mouse model of Osteoarthritis decreases disease burden (Zheng et al. 2018). Our data indicate that TFEB level decrease with age in human peripheral blood mononuclear cells, and TFEB levels can be increased by spermidine to reverse the ageing phenotype of these cells (Alsaleh et al. 2020). In this project we will study the impact of TFEB on cellular senescence of joint tissues and how this pathway contributes to OA disease. The aim is to harness TFEB as a drug target by using state-of-the-art techniques to assess TFEB expression and specific age-related phenotypes in the joint tissue in OA preclinical models and from OA patients.
Osteoarthritis, autophagy, TFEB, ageing, Drug screen.
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 and cell cultures such as 2D and 3D of primary culture cells, isolation, and culture of human chondrocytes and synoviocyte fibroblasts, cell line culture and animal models and finally drug screen design assay. 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 to 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 collaborating groups in The Centre for Osteoarthritis Pathogenesis Versus Arthritis (OA Centre), Oxford, DRFZ Institute, Berlin, TIGEM Institute, Naples and The Buck Institute for ageing research, 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 and run by the IT department (information will be provided once accepted to the programme).
- Zhang, H., Alsaleh, G., Feltham, J., Sun, Y., Napolitano, G., Riffelmacher, T., Charles, P., Frau, L., Hublitz, P., Yu, Z., Mohammed, S., Ballabio, A., Balabanov, S., Mellor, J. and Simon, A. K. Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. Mol Cell.2019. (LINK)
- Zheng, G., Zhan, Y., Li, X., Pan, Z., Zheng, F., Zhang, Z., Zhou, Y., Wu, Y., Wang, X., Gao, W., Xu, H., Tian, N. and Zhang, X. TFEB, a potential therapeutic target for osteoarthritis via autophagy regulation. Cell Death Dis. 2018. (LINK).
- Alsaleh, G., Panse, I., Swadling, L., Zhang, H., Richter, F. C., Meyer, A., Lord, J., Barnes, E., Klenerman, P., Green, C. and Simon, A. K. Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. eLife. 2020. (LINK)
Ageing, Arthritis, Immunology.
Details of the supervisors and research group
Dr Ghada Alsaleh is a new PI at the Botnar institute, and her group will include one RA and one PhD student. Dr Alsaleh has significant experience in student's supervision, having co-supervised three D.Phil students at Oxford University. Dr Alsaleh works closely with Professor Christopher Buckley’s group, the 2nd supervisor.
- The Centre for Osteoarthritis Pathogenesis Versus Arthritis (OA Centre)
- Dr. Carmine Settembre, the Telethon Institute of Genetics and Medicine (TIGEM)
- Prof. Dr. Max Löhning, Pitzer Laboratory of Osteoarthritis Research Charité - Universitätsmedizin Berlin (CCM) Department of Rheumatology and Clinical Immunology German Rheumatism Research Center (DRFZ).
- Prof. Judith Campisi, the Buck Institute for ageing research, California.
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 Officer, Sam Burnell, 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 or MSc by research will commence in October 2022.
Applications should be made to one of the following programmes using the specified course code:
D.Phil in Musculoskeletal Sciences (course code: RD_ML2)
MSc by research in Musculoskeletal Sciences (course code: RM_ML2)
D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)
MSc by research in Molecular and Cellular Medicine (course code: RM_MP1)
For further information, please visit the University Graduate Study page.
Dr Ghada Alsaleh