Supervisor View Full Details

• genetics, genomics and molecular biology

• Medicine

• Rheumatology

My research is centred on understanding genetic and epigenetic influences on the severity of tissue damage in rheumatoid arthritis (RA). These studies have involved using well characterised RA populations from around Europe having both radiological damage scores (Larsen or SHS) and genome-wide genetic data. Functional studies use synovial and leucocyte cells from RA patients, and the CIA model.
We have identified genetic variants associated with severity of radiological damage in immune-related loci including DRB1, C5-TRAF1, TNFAIP3, IL-4 and IL-15 (1-3). In addition we have identified C5orf30 as a novel regulator of tissue damage and inflammation in RA (4, 5), it is expressed predominantly by RA synovial fibroblasts (RASF) and macrophages. RASF are key mediators of cartilage damage in RA via the production of proteases. These cells have a semi-transformed, auto-aggressive phenotype and in vitro activities, such as invasiveness, correlates with rate of radiological progression in individual RA patients.

Key recent references
1. Arthritis Rheum. 2013;65(3051-7.
2. JAMA. 2015;313(16):1645-56.
3. Ann Rheum Dis. 2012;71(10):1651-7.
4. Arthritis Rheum. 2013;65(10):2555-61.
5. Proc Natl Acad Sci U S A. 2015;112(37):11618-23.

The central hypothesis is that the auto-aggressive phenotype of RASF correlates with the severity of joint damage in individual RA patients. Cells will be obtained from knee joint synovial biopsies and studies will be performed to assess key biological activities in vitro including: invasiveness (Matrigel assay), migration (Scratch assay), proliferation (tritiated-thymidine incorporation), apoptosis (annexin V/propidium iodide staining. Genotyping of variants linked with joint damage will be determined using Taqman assays and correlates between genotype and RASF phenotype determined. Gene expression differences will be compared between genotypes using expression arrays and qPCR. If novel mediators are identified in genetic screens these will be studied using additional techniques in human and murine models systems that are already used in the group (1, 2).
The researcher will work within a team of clinical and laboratory scientists and gain extensive experience in molecular and cellular biology, statistical analysis and joint arthroscopy. The findings arising from this study will include novel insights into the mechanisms linking RA-inflammation with joint tissue damage and may also result in the identification of novel mediators that could be potential therapeutic targets. The data will be presented at national and international rheumatology and immunology conferences and result in publications in high impact factor journals.

References
1. Proc Natl Acad Sci U S A. 2015;112:11618-23.
2. Hum Mol Genet. 2015;24:5367-77.