Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune condition, which presents with fatigue, arthritis, scarring skin rashes and organ damage, especially kidney failure. Current treatment relies on corticosteroids and immunosuppressives, which cause significant side effects. In SLE, toll-like receptor-7 (TLR7) stimulation induces plasmacytoid dendritic cells to secrete excessive amounts of the cytokine interferon-alpha. In conjunction with other mechanisms, interferon-alpha drives B cells to produce autoantibodies, which lead to tissue damage. However the regulation of interferon-alpha secretion by plasmacytoid dendritic cells is poorly understood.
UBE2L3 is an E2 ubiquitin-conjugating enzyme which is strongly linked to causing systemic lupus erythematosus (SLE) through genetic studies. We propose that UBE2L3 promotes interferon-alpha secretion by plasmacytoid dendritic cells through ubiquitination and degradation of NRF2, a negative regulator of inflammation, and increased expression of Stimulator of Interferon Genes (STING). To validate this model, we will:
- Correlate UBE2L3 expression and genotype and NRF2 expression with plasmacytoid dendritic cells secretion of interferon-alpha in SLE patients.
- Assess the effect of the UBE2L3 inhibitor dimethyl fumarate (DMF) on interferon-alpha secretion by plasmacytoid dendritic cells.
- Use gene targeting by siRNA library screen, lentiviral shRNA and/or CRISPR to dissect the pathways and mechanisms underlying the effect of UBE2L3 on NRF2 and STING signalling.
This study aims to provide evidence to support repurposing the UBE2L3 inhibitor DMF as a novel SLE therapy.
The PhD studentship is hosted at the Centre for Experimental Medicine & Rheumatology (EMR), Barts School of Medicine, Queen Mary University of London (QMUL), which is internationally known for translational rheumatology research. EMR provides a base of operations for over 50 scientists & clinicians, including national multi-centre clinical trials funded by MRC, NIHR & Versus Arthritis. At Barts, inflammation has been identified as a major research area, where rheumatology stands as a research strand of excellence. QMUL offers mentoring and many pastoral opportunities to fully support training. This combination of worldwide clinical expertise with extensive laboratory infrastructure and established collaborations makes Barts an ideal and dynamic environment for high quality translational research.
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