Kennedy Trust Prize Studentships
The molecular function of retinoic acid in human hand osteoarthritis
Hand osteoarthritis (OA) is a highly prevalent and debilitating condition that affects more than 1.3 million people in the UK. It mostly affects women, particularly around the time of the menopause and causes substantial pain and disability. There is a strong heritable component to hand OA, and a recent GWAS study has identified common hypomorphic variants in ALDH1A2 in individuals with severe hand OA . The ALDH1A2 gene encodes an enzyme involved in the biosynthesis of all-trans retinoic acid (atRA). Preliminary data from our group has demonstrated that atRA is highly expressed in normal adult cartilage and is strongly regulated by mechanical injury, the most important driver of osteoarthritis, . Increasing the levels of atRA pharmacologically suppresses the inflammatory response to injury, indicating that it has an anti-inflammatory role in vivo.
We have been able to extract mRNA from the cartilage of patients with hand OA and have stratifed the patients according to whether they are homozygous or wild type for the ALDH1A2 polymorphism (variant occurs in around 50% of the hand OA population). This project will use RNA-seq techniques to analyse the molecular profiles in hand OA patients with and without the polymorphic variant to identify the role that atRA plays in driving clinical disease.
The student will be embedded within the Arthritis Research UK Centre for OA Pathogenesis at the Kennedy Institute, a world-renowned research centre housed in a new state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend external scientific conferences where they will be expected to present their research findings.
- U. Styrkarsdottir, G. Thorleifsson, H. T. Helgadottir, N. Bomer, S. Metrustry, S. Bierma-Zeinstra, A. M. Strijbosch, E. Evangelou, D. Hart, M. Beekman, A. Jonasdottir, A. Sigurdsson, F. F. Eiriksson, M. Thorsteinsdottir, M. L. Frigge, A. Kong, S. A. Gudjonsson, O. T. Magnusson, G. Masson, TREAT-OA Consortium, arcOGEN Consortium, A. Hofman, N. K. Arden, T. Ingvarsson, S. Lohmander, M. Kloppenburg, F. Rivadeneira, R. G. H. H. Nelissen, T. Spector, A. Uitterlinden, P. E. Slagboom, U. Thorsteinsdottir, I. Jonsdottir, A. M. Valdes, I. Meulenbelt, J. van Meurs, H. Jonsson, and K. Stefansson, “Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31.,” Nat. Genet., vol. 46, no. 5, pp. 498–502, May 2014.
- T. L. Vincent, “Targeting mechanotransduction pathways in osteoarthritis: a focus on the pericellular matrix.,” Curr Opin Pharmacol, vol. 13, no. 3, pp. 449–454, Jun. 2013.
- A. Burleigh, A. Chanalaris, M. D. Gardiner, C. Driscoll, O. Boruc, J. Saklatvala, and T. L. Vincent, “Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo.,” Arthritis Rheum., vol. 64, no. 7, pp. 2278–2288, Jul. 2012.
- Genes, Genetics, Epigenetics and Genomics; Musculoskeletal Science; Translational Medicine and Medical Technology; Ageing, Geratology and Degenerative Disease.
Contact: Professor Tonia Vincent, Kennedy Institute of Rheumatology, University of Oxford.