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Kennedy Trust Prize Studentships

  • Project No: KTPS-RACE-1
  • Intake: 2021 RACE

PROJECT OUTLINE

Rheumatoid arthritis (RA) is a systemic inflammatory disease, the hallmark of which is the destruction of the joint tissues where inflamed synovial tissue invades and destroys cartilage and bone, leading to disability. The functionality of cartilage is mainly relying on the nature of the major extracellular matrix components: type II collagen, that provides tissue architecture, and aggrecan, providing compression-resistant property to the tissue. In RA, these ECM components are degraded by proteolytic enzymes produced from synovial cells. We have previously identified MT1-MMP, a membrane-anchored collagenolytic metalloproteinase, as the responsible enzyme that destroys the cartilage by degrading collagen (ref 1, 2, 3). Our study has shown that the treatment of arthritic mice with a selective inhibitor of MT1-MMP together with anti-TNF synergistically inhibited the progression of arthritis, suggesting that MT1-MMP-mediated cartilage destruction can be an excellent therapeutic target (ref 3). Recently we discovered that one of the common coding single nucleotide polymorphisms (SNP) variant of MT1-MMP possesses significantly lower collagen degrading activity (around 17 % of wild-type MT1-MMP). Our study indicated that myofibroblasts carrying one allele of SNP express only 30% collagen degrading activity compared to the cells without the SNP allele, suggesting that carrying the one SNP allele is enough to reduce cellular collagen degrading activity in a significant manner (ref 4). Genome aggregation database indicates that around 35% of the European population carries at least one allele of this SNP. Since there is no correlation between the SNP and RA disease onset, it is expected that around 35% of RA patients are likely to carry the SNP allele, and we hypothesize that these patients may display milder disease phenotypes, i.e., cartilage erosion.  Specifically the project involves

1. Collection of RA synovial cells derived from patients and genomic analysis. Different synovial fibroblasts from patients will be collected and genotype the SNP allele. Ideally, 20-30 lines each genotype should be corrected.

2. Investigate the correlation of the genotype and disease progression, histological phenotypes, and flare.Using the available cohort database and samples and information obtained together with the collected synovial cell samples above, investigate if the SNP genotypes correlate with disease progression, histological phenotype, and flare.

3. Functional assay of collected synovial fibroblasts with different genotypes. Synovial cells collected in project 1 will be examined for MT1-MMP functions, including proMMP-2 activation, collagen film degradation, and collagen invasion activities. This data may correlate with the data in Project 2.

4. Investigate the cause of the reduced collagenolytic activity of the SNP variant. It is not clear why SNP variant MT1-MMP displays much lower collagenolytic activity. Our data indicated that reduced cell surface collagenolytic activity is not due to the decrease of intrinsic collagenolytic activity but likely due to different cellular effects. If so, MT1-N273 may have different molecular interactions on the cell surface, which may result in lower cell surface collagenolytic activity. We will thus investigate the interactome of MT1-D273 and N273 by proximity labelling proteomics approach using BioID2.

TRAINING OPPORTUNITIES

The Kennedy Institute is a world-renowned research centre and is housed in a state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques and animal studies. 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 the research findings. 

KEY PUBLICATIONS

  1. Itoh Y. (2015) Membrane-type matrix metalloproteinase: their function and regulations. Matrix Biol. vol 44-46, pp207-23
  2. Miller, M. C., Manning, H. B., Jain, A., Troeberg, L., Dudhia, J., Essex, D., Sandison, A., Seiki, M., Nanchahal, J., Nagase, H., and Itoh, Y. (2009) Membrane-type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritis. Arthritis Rheum 60, 686-697
  3. Kaneko K, Williams RO, Dransfield DT, Nixon AE, Sandison A and Itoh Y (2016) Selective inhibition of membrane type 1 matrix metalloproteinase abrogates progression of inflammatory arthritis: synergy with TNF blockade. Arthritis Rheum 68 (2), 521-531
  4. Itoh Y, Ng M, Wiberg A, Inoue K, Hirata N, Paiva KBS, Ito N, Dzobo K, Sato N, Gifford V, Fujita Y, Inada M, Furniss D. (2020) An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren’s Disease. bioRxiv 2020.06.09.142513;https://doi.org/10.1101/2020.06.09.142513

KEYWORDS

Rheumatoid arthritis; cartilage erosion; MT1-MMP; MT1-MMP SNP; collagen degradation.

Contact

Yoshi ItohKennedy Institute, University of Oxford

 

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