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NDORMS DPhil & MSc by Research

OUTLINE OF RESEARCH PROPOSAL

Dupuytren's disease (DD - OMIM 126900) is a progressive fibroproliferative disease of the palmar fascia, which results in flexion contractures of the involved digits, and significant functional impairment. DD is very common, and affects males more commonly than females. In England alone, we perform over 15,000 operations for Dupuytren's Disease per year, and this number is increasing.

The pathophysiological basis of DD is complex and incompletely understood. The key pathological cell is thought to be the myofibroblast, though there is increasing evidence that inflammatory cells such as macrophages and mast cells are important, with the TNF signalling pathway interacting with WNT signalling.

A genetic predisposition to DD is well recognised. We have demonstrated a sibling recurrence risk of 4.5, and a recent twin study reported a heritability of 0.8. DD has been demonstrated to be a complex disease, where multiple genetic and environmental factors affect overall genetic predisposition.

A pilot genome-wide association study (GWAS) in DD was published in 2011, wherein 9 loci predisposing to DD were identified, six of which harboured genes involved in WNT signalling. We have recently completed a second phase GWAS in a total of 8220 cases and 12874 controls. We have identified 24 genetic loci predisposing to DD (in preparation). One of these 24 variants, rs1042704 (p=7.11 x 10-14), is a non-synonymous coding variant in MT1-MMP, also known as MMP14. MT1-MMP is a membrane-bound matrix metalloproteinase that promotes cellular invasion by degrading pericellular extracellular matrix.

Furthermore, MT1-MMP has been shown to have diverse functions such as regulating the macrophage inflammatory response, regulating Notch signalling in bone marrow stromal cells, and regulating myoblast fusion via processing various cell surface molecules. It has physiological roles in embryonic development and wound healing, and pathological roles in tumour invasion, atherosclerosis, angiogenesis and rheumatoid arthritis, amongst others.

The role of MT1-MMP in DD has not been fully elucidated, though its expression has been shown to be regulated by matrix tension, and inhibition of MT1-MMP reduces matrix contraction. We hypothesize that a variant affecting the function of MT1-MMP predisposes to DD, and that MT1-MMP is therefore a key transmembrane protein in the development of fibrosis.

Furthermore, we hypothesise that modulation of MT1-MMP can alter the fibrotic response in DD tissue, and potentially in other fibrotic conditions, leading to the potential development of new therapeutic options. During your DPhil, you will re-analyse imputed genetic and ATAQseq data to generate a 99% credible set for the predisposing variant(s) at this locus. The effect of these variants on MT1-MMP function will be analysed by site-directed mutagenesis in a well-established system.

The precise nature of the experiments will be dependent on the location of the pathogenic variant, but you will explore areas such as the effect of MT1-MMP mutants on TNF signalling; the interaction of MT1-MMP with the WNT signalling apparatus; the effects of MT1-MMP mutants on cell migration and collagen turnover. You will also investigate the effects of specific inhibitors of MT1-MMP on DD patient derived cells.

TRAINING OPPORTUNITIES

This DPhil will provide training in molecular biology techniques such as PCR, site-directed mutagenesis, immunocytochemistry and immunohistochemistry, co-immunoprecipitation, the use of siRNA and overexpression vectors, and more advanced techniques such as FRET. Bioinformatic and statistical training will also be provided, as will training in transferrable generic skills such as data handling, presentation and writing skills, and time management.

THEMES

  • Genetics
  • Cell signalling
  • Matrix biology

FURTHER INFORMATION

Professor Dominic Furniss
dominic.furniss@ndorms.ox.ac.uk

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