This PhD opportunity will focus on the role of sex steroids (androgens and oestrogens) on the immune function in patients with rheumatoid arthritis. The project will be split into 3 defined Work Packages (WP).
WP1: Immune function pathway analysis in rheumatoid arthritis: correlation with sex steroid metabolism.
The student will explore existing datasets to explore how the inflammatory regulation of sex steroid bio-availability impacts immune function in rheumatoid arthritis (RA). We have developed comprehensive data sets that will give insights into the sex steroid metabolism pathways in numerous immune cells in human RA patients. These resources will undergo pathway analysis to identify novel sex steroid metabolism that impacts RA severity and outcomes.
WP2: Androgen metabolism and action and its effect on RA pathophysiology.
Evidence exists suggesting a potential role for androgen metabolism in RA patients. However, there has been very little examination of the potential role androgen metabolising enzymes and receptors play in RA development and severity. This work package will examine how androgens and their metabolism pathways influences these aspects of RA. Using human primary macrophages and fibroblasts taken from synovial fluid of RA patients, the expression of androgen metabolism enzymes and the androgen receptor will be determined. How specific androgens influence fibroblast survival will be examined, and how androgens augment or depress inflammatory signalling will also be determined. Furthermore, how macrophages and fibroblasts metabolise androgens will be measured through state-of-the-art LC-MS/MS available through collaboration with the IMSR Steroid Metabolome Analysis Core (SMAC).
WP3: Oestrogen metabolism and its effect on RA pathophysiology.
Similar to WP2 above, this WP will examine the potential role of oestrogens and their metabolism pathways on inflammatory outcomes in RA patients. in this WP the expression patterns of oestrogen metabolism enzymes and the oestrogen receptors will be examined in macrophages and fibroblast from RA patients.
Expect Outcomes
This PhD project will provide in-depth insights into sex steroid metabolism in cell types involved in RA. As there is limited understanding of the intracrinology in RA and how this impacts disease severity, this proposal will shed light on this area and possibly indicate potential novel avenues for improved therapy. Data obtained would be used to support further funding applications in this area specifically to the MRC and the charity Versus Arthritis.
Supervisor team
This PhD will be split between Dr Paul Foster (50%) and Dr Rowan Hardy (50%). Dr Foster is an expert in sex steroid metabolism in different disease states. His research is heavily drug discovery focused and he has been involved in the successful development of anti-cancer compounds that have reached Phase II clinical trials. Dr Foster also has experience in inflammatory mediators and their potential impact on steroid metabolism in cancer. Dr Foster has significant experience in supervising PhD, MRes, MSc, and BMedSci post-graduate and undergraduate students.
Dr Hardy’s research examines the roles of myeloid and mesenchymal steroid metabolism and signalling in mediating inflammatory disease pathophysiology and systemic complications in muscle and bone, identifying novel strategies to improve the safety profile of therapeutic glucocorticoids. This research involves world leading national and international collaboration across multiple centres of excellence at the University of Birmingham, including the MRC/Versus Arthritis Centre for Musculoskeletal Ageing Research (CMAR), and the Birmingham Biomedical Research Centre (BRC).
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