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Targeting TFEB for the treatment of Osteoarthritis. (KTPS-Clinical-5)


Kennedy Institute of Rheumatology

About the Project

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 TFEB, a master regulator of autophagy and lysosomal biogenesis, the main cellular bulk degradation pathway, in immune senescence (Zhang, Alsaleh et al). 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, eLife final revision). 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.

TRAINING OPPORTUNITIES:

The project provides unique training opportunities in various techniques such as 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. You will benefit from the KIR’s state-of-the-art core facilities, including the osteoarthritis centre where you will have access to the highly experienced animal technicians that work on osteoarthritis. You will benefit from an international and multidisciplinary environment with world-leading specialists in arthritis and ageing research and as a member of the University of Oxford, you will have access to the most up-to-date literature and collaborations within the institution, with quick and easy access to state-of-the-art platforms and experimental expertise. You will attend regular seminars within the department and in the wider University. You will benefit from daily supervision, and you will be expected to present data regularly in lab meetings and in departmental progress report seminars and in national and international conferences. You will have the opportunity to work closely with collaborating groups in DRFZ Institute, Berlin, TIGEM Institute, Naples and The Buck Institute for ageing research, California.


References

1. Alsaleh G., Panse I., Zang H., Swadling L., Green C., Meyer A., Klenerman P and Simon AK. Autophagy as a pathway to rejuvenate immune responses in human T cells. eLife under final revision.
2. Zang H., Alsaleh G., Feltham J., Sun Y., Riffelmacher T., Charles P., Faru Lisa., Yu Z., Mohammed S., Balabanov S., Mellor J and Simon AK. Translational control of TFEB and autophagy via eIF5Arejuvenates B cell immunity. Mol Cell. 2019.
3. Sacitharan, P. K., Lwin, S., Gharios, G. B. & Edwards, J. R. Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300. Exp Mol Med. 2018. 50, 123, doi:10.1038/s12276-018-0149-3.
4. Zheng, G. et al. TFEB, a potential therapeutic target for osteoarthritis via autophagy regulation. Cell Death Dis. 2018. 9, 858, doi:10.1038/s41419-018-0909-y.


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