About the Project
The mammalian synovial joint is a dynamic organ comprised of distinct tissues designed to enable limb articulation and facilitate free movement. Whilst often considered a grouping of distinct tissues in close physical proximity, there exists extensive crosstalk between the synovium, cartilage, and intraarticular adipose tissue. Poor musculoskeletal ageing is one of the biggest contributors to years lived in poor health and loss of work years. Osteoarthritis (OA) is one of the biggest…
contributors to this, affecting over 10 million adults in the UK alone. OA was, for a long time, considered an age-associated “wear and tear” disease, an inevitable consequence of ageing leading to the breakdown of articular cartilage and exposure of the underlying subchondral bone. This gross misconception has hindered the field: to date no disease-modifying drugs for OA have been identified.
Genetics are one of the biggest risk factors for OA. OA genetic risk variants can either act in a specific way (in single joint-sites or cell-types) or in a pleiotropic manner (common mechanisms across cell types and joint sites). This has profound implications on translational potential yet remains poorly understood. Amongst the pleiotropic variants, further biological complexity exists. In this project, the student will investigate the influences on pleiotropic osteoarthritis GWAS variants, through three different perspectives:
- Individual genetic signals mediating the opposite differential expression of the same target gene between tissues of the same joint (biological pleiotropy).
- Individual risk signals mediating differential gene expression during human development. Such mechanisms have often undergone evolutionary selection to allow the adaptation of the human skeleton but can have detrimental effects on skeletal ageing (antagonistic pleiotropy).
- A single OA risk signal with different target genes in distinct OA joint cell-types, both potentially contributing to disease risk through independent mechanisms (synergistic pleiotropy).
To conduct this work, the successful candidate will apply leading genomic and epigenomic technologies in human primary joint cells from the hip and knee of adult osteoarthritis patients, and from the developing human (foetal) skeleton. This will be followed by downstream bioinformatic analysis using R pipelines, and functional validation of regions of interest in the lab using targeted techniques such as reporter assays and pyrosequencing. The student will receive extensive training in primary cell isolation and culture, bioinformatic analyses, and advanced molecular biology techniques including CRISPR-Cas9 and dCas9 epigenome editing.
This project is anticipated to generate translational targets for intervention in osteoarthritis, improving our understanding of when (in the life course) and where (cell-type and joint-site) treatment would be most effective.
Eligibility
Applicants are expected to hold (or about to obtain) a minimum upper second class undergraduate honours degree (or equivalent) in a relevant biological field. Theoretical knowledge of genetics and epigenetics along with bioinformatic expertise is desirable.
How to Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Interested candidates must first make contact with the Primary Supervisor prior to submitting a formal application, to discuss their interest and suitability for the project. On the online application form select PhD Musculoskeletal.
Application deadline: Friday 9th October at 5pm.
If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester.
Funding Notes
School of Biological Sciences Studentship.
Studentship funding is for a duration of three years to commence in January 2027 and covers UK tuition fees and an annual stipend (UKRI rate).
References
McDonnell E, Orr SE, Barter MJ, Rux D, Brumwell A, Wrobel N, Murphy L, Overman LM, Sorial AK, Young DA, Soul J, Rice SJ (2024) The methylomic landscape of human articular cartilage development contains epigenetic signatures of osteoarthritis risk. American Journal of Human Genetics, 111(12):2756-2772.
Rice SJ, Brumwell A, Falk J, Kehayova YS, Casement J, Parker E, Hofer IMJ, Shepherd C, Loughlin J (2023). Genetic risk of osteoarthritis operates during human skeletogenesis. Human Molecular Genetics, 19;32(13):2124-2138.
Kehayova YS, Wilkinson JM, Rice SJ*, Loughlin J (2023) Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues. Arthritis Research & Therapy, 19;25(1):83.
Kehayova YS, Wilkinson JM, Rice SJ, Loughlin J (2023). Independent osteoarthritis risk-conferring alleles mediate the same epigenetic and transcriptional effect on a shared target gene, COLGALT2. Arthritis and Rheumatology, 75(6):910-922.
Rice SJ, Young DA, Beier F, Loughlin J (2020) Interplay between genetics and epigenetics in osteoarthritis. Nature Reviews Rheumatology, 16, 268-281.
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