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  • Project No: #OxKEN-2022/5
  • Intake: OxKEN 2022

PROJECT OVERVIEW

Worldwide, 20-33% of people live with painful and disabling musculoskeletal diseases. Diseases occur in all joints and particularly affect soft tissues especially the tendons, synovium, ligaments or fibrocartilage. While functionally diverse, these soft tissues possess a rich extracellular matrix (ECM), low cellularity and a predilection for ‘degeneration’ and consequent structural failure. Such pathologies are particularly prevalent in the knee, meniscal fibrocartilage or anterior cruciate ligament (ACL) tears each have an annual incidence of 60-70 cases per 100,000 people and pre-dispose to osteoarthritis. Blood vessel ingrowth, fibrosis, significant presence of inflammatory mediators and immune cell infiltration hallmark ‘degenerative’ soft tissue joint diseases – strongly implicating chronic inflammation in their onset and progression. However, it is unclear if shared or unique inflammatory processes underpin these clinically distinct diseases. 

Unravelling the single cell signatures and molecular processes driving autoimmune joint diseases has revolutionised therapeutic development and repurposing. The lack of equivalent, comprehensive, assessment of the landscape underpinning ‘degenerative’ joint diseases limits treatments to broad-spectrum anti-inflammatories and surgical repair. Such therapies are at best ineffective and at worst harmful. The laboratory challenges of working with ECM-rich tissues and the clinical challenges of accessing tissues for delivery of representative cellular atlases has compounded current efforts to treat these diseases. Further, a paucity of pre-clinical models that recapitulate disease further hampers successful development of pharmacologic and surgical-biomaterial treatments for ‘degenerative’ diseases of the knee.  

Goals

This mixed-methods project focuses on the knee, delivering an ethnically diverse comparative single-cell portrait of inflammation-driven degenerative soft tissue joint diseases of the knee, with concomitant development of in-vitro disease models. We will: 

  1. Generate comparative and ethnically diverse single cell maps of diseased (torn) and healthy patellar tendon, meniscus and ACL, and osteoarthritic synovium. Single nucleus RNAseq (SNucRNAseq) and imaging will identify the unifying and unique cellular features underlying knee soft tissue homeostasis and inflammation-driven disease. 
  2. Develop scalable, tractable and physiologically relevant in-vitro models of diseased soft tissues. We will culture human fibroblasts and immune cells on our synthetic, ECM-mimicking electrospun (naive and growth factor functionalised, and hydrogel biomaterials. We will assess which of these cell-instructive biomaterials best induce recapitulation of the unifying and unique cellular signatures (WP1) of inflammation-driven degenerative diseases of knee soft tissues. 
  3. Concurrently analyse a national survey to exploring factors influencing participation in musculoskeletal tissue biobanking. This survey explores a number of domains including; privacy, autonomy, religious belief, monetary or health considerations and research design. The results of this survey will be used to build a focus group and improved educational material to better support ethnically diverse patients to participate in research.

Ultimately we aim to revolutionise the development and testing of effective treatments for inflammation-driven ‘degenerative’ soft tissue joint diseases (collaboration with Prof Duncan Richards and Prof Chris Buckley). Critically we aim for these advances to be developed to clearly benefit ethnically under-represented populations.

KEYWORDS

Genomics, inflammation, ethnicity, musculoskeletal

TRAINING OPPORTUNITIES

Alongside departmental training opportunities listed below we will ensure hands-on computational training to support analysis of single-cell RNAseq data and embedding within our international Tendon Seed Network to ensure laboratory guidance and support. The student will work on their unique project within an experienced and collaborative team. The qualitative work within this project will be supported by long-standing collaborations with our population health and clinical trial unit partners. A student would be supported to shadow relevant clinical work and to attend clinical and basic science conferences to enrich their studies –financial support is available for travel to conferences.

NDORMS hosts Oxford's Institute of Musculoskeletal Sciences, a centre for experimental medicine, the Kennedy Institute of Rheumatology and a specialist trauma research unit. This enables and encourages research and education into the causes of musculoskeletal disease and their treatment.

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. All students are also required to attend a 2-day Statistical and Experimental Design course at NDORMS. Students will also be required to attend regular seminars within the Department and have access to a variety of other courses run by the Medical Sciences Division Skills Training Team and the wider University.

Finally, the student(s) will be expected to regularly present data in Departmental seminars, the Soft Tissue Repair group and within our linked groups including the Oppermann, Cribbs and Buckley teams.

KEY PUBLICATIONS

  1. Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism. Cribbs et al. Proceedings of the National Academy of Sciences Mar 2020, 117 (11) 6056-6066; DOI:10.1073/pnas.1919893117
  2. Factors influencing public participation in biobanking. Ahram et al. Eur J Hum Genet. 2014;22(4):445-451. doi:10.1038/ejhg.2013.174
  3. Augmenting endogenous repair of soft tissues with nanofibre scaffolds. Baldwin et al. J. R. Soc. Interface.2018.  http://doi.org/10.1098/rsif.2018.0019 

CONTACT INFORMATION OF ALL SUPERVISORS

Sarah Snelling

Matthew Baldinw

Adam Cribbs

Christopher Buckley