1997-1998. ARC Post-doctoral Research Assistant, Wellcome Trust Centre for Matrix Research, University of Manchester.
1998-2003. ARC Senior Post-doctoral Research Assistant, School of Biological Sciences, University of East Anglia.
2003-2004. Dunhill Medical Trust Post-doctoral Research Assistant, School of Biological Sciences, University of East Anglia.
My research interests include the expression and regulation of metalloproteinases (MPs) and their inhibitors the TIMPs, particularly in the context of osteoarthritis (OA). My laboratory focus is how these genes are epigenetically regulated; by microRNAs, DNA methylation and chromatin modifications.
We are also investigating the role of mitochondria and the role of ubiquitination in OA.
Main techniques: Gene expression analysis/profiling (Real-time PCR, Taqman Low density arrays, microarray, RNA-seq). Cell signalling analysis. RNAi (siRNA, shRNA). miRNA analysis. Cas9/CRISPR. Transcription factor analysis (EMSA, mutagenesis, reporter assays). Epigenetic analysis. Models of osteoarthritis.
My laboratory will research the mechanisms by which HDACi block MP expression, determine the signalling pathways/mechanisms and identify the HDACs involved.
Age is the major risk factor for Osteoarthritis. Little is known about the changes within cartilage with age. Cellular senescence is the phenomenon where cells lose the ability to divide. There is currently weak data showing that chondrocytes, the cells of cartilage senesce. We are testing whether chondrocytes do senesce and what the causes and consequences of this senescence are.
We have pioneered siRNA technology within the collaborative group to both the key cartilage degrading MPs and the HDACs identified above and are developing methods to deliver these to intact cartilage explants. The generation of quantitative real-time RT-PCR primers and probes for the bovine collagenase, gelatinase and aggrecanase homologues will provide a useful resource for the collaborative group as a whole.
British Society for Matrix Biology (BSMB) Honorary Treasurer
Current funding is mainly from the JGW Patterson Foundation, Arthritis Research UK, CIMA and the Nufflied Oliver Bird Rheumatism Programme.
More than 7 million adults in the UK (15% of the population) have long-term health problems due to arthritis and related conditions. In 2001 incapacity benefit alone cost the nation £2.4 billion.
Metalloproteinases are the enzymes ultimately responisble for the collagen loss to cartilage seen in arthritic diseases. The design of small molecule inhibitors of the metalloproteinases remains a major focus of the pharmaceutical industry, yet has been largely unsuccessful, probably due to a lack of specificity of the compunds and side effects. Since arthritis is a debilitating, but not fatal disease, such side effects need to be minimised. We suggest that HDACi will be chondroprotective in all destructive arthritides, including both rheumatoid arthritis and osteoarthritis (other examples include: reactive arthritis, gout/pseudogout, psoriatic arthritis). They may also show utility in cartilage engineering/transplantation to protect cartilage explants or engineered/cultured cartilage from degradation. Many pharmaceutical companies are currently testing HDACi in cancer therapy trials, therefore these molecules potentially represent the next wave of drugs to fight the arthides.
I regularly supervise MRes/BSc students for laboratory projects and lecture on the MRes Biology or Ageing and Current trends in musculoskeletal disease modules.
I am a PG detupy co-ordinator.
I oversee MRes projects