About the Project
Juvenile-onset systemic lupus erythematosus (JSLE) is characterized by more severe symptoms and less favorable outcomes when compared to adult-onset SLE (aSLE). JSLE patients exhibit variable presentations and outcomes, and age inversely correlates with disease severity. Identifying age- and outcome-specific biomarkers may help to diagnose JSLE patients, predict prognoses, measure disease activity, and identify pathomechanisms and treatment targets.
Project Aims: Planned experiments will deliver biomarkers that may be age-specific, provide tools for activity and outcome assessment, and improve our pathophysiological understanding.
Scientific Objectives:
1) Quantification of S100A8/9 and S100A12 in serum and urine. Proteins S100A8/A9 and S100A12 are released from monocytes and/or granulocytes during activation of the innate immune system. They are considered valuable biomarkers in several paediatric inflammatory diseases, and promise potential as routine laboratory parameters. S100 proteins directly contribute to inflammation through their ability to activate TLR2 and may be targets in future therapeutic approaches(2). S100A8/A9 play a role during glomerulonephritis, exerting and amplifying autocrine and paracrine pro-inflammatory effects on renal endothelia(3).
Hypothesis: S100 proteins may be particularly useful for patient stratification and the assessment of disease activity. Since S100 proteins are produced by renal endothelia, urine levels of S100 proteins may be suitable indicators or kidney inflammation. We propose that the expression and release of S100 proteins (serum and urine) may reflect inflammatory activity, response to treatment, indicate subtypes of SLE, and/or predict clinical outcomes. We will quantify S100 proteins in the serum and urine of patients using LUMINEX-based approaches and integrate findings with clinical datasets.
2) Serum and urine expression of non-coding RNAs. More than 80% of the human genome is transcribed into RNA with little or no protein-coding capability. Noncoding RNA (ncRNA), including miRNA and long-noncoding RNA (lncRNA) have emerged as important regulators of biological functions. ncRNA expression occurs at the interface between the transcription of genes, chromatin remodelling, and the translation of messenger RNA into protein products, regulating approximately 30% of human genes(4). Studies demonstrated associations between both miRNA and lncRNAs and autoimmune disease(5). Circulating ncRNAs can be detected in the serum and urine of patients with autoimmune disease promising potential as biomarkers. Indeed, urinary miRNAs have been previously quantified in urine samples from patients with biopsy-proven lupus nephritis(6).
Hypothesis: The expression of ncRNAs may correlate with organ involvement and disease outcomes. Furthermore, ncRNAs likely contribute to gene dysregulation and are the effect of altered epigenetic patterns in SLE. Thus, circulating ncRNAs may not only act as disease biomarkers and allow patient stratification, but may also deliver previously not know pathomechanisms and therapeutic targets. We will determine ncRNA expression in the serum and urine using RNASequ. or lncRNA/miRNA arrays, followed by integration with clinical datasets.
Training and Support:
• The Ph.D. student will be based in state-of-the-art laboratory facilities in the ‘Institute in the Park’ that guarantee access to a wide range of equipment, allowing for the execution of outlined experiments. The proximity to Alder Hey Children’s Hospital is particularly beneficial given support from the NIHR Alder Hey Clinical Research Facility (Director: Beresford) including trained staff collecting bio-samples.
• The study will be supported by the Department of Paediatric Rheumatology, the UK’s Experimental Arthritis Treatment Centre for Children (Director: Beresford), the UK JSLE Cohort Study and Bio-repository (CI-Beresford), the LUPUS UK ‘Centre of Excellence for Childhood Lupus’, and which will support access to bio-samples.
• The student will also be supported by the EATC4Children’s PDRAs on a day-to-day basis
• The student will be co-supervised by Professors Michael W. Beresford and Christian M. Hedrich with extensive experience with patient-focused immunological studies, supported by post-doctoral scientists. The research group is experienced in necessary laboratory techniques and will offer full support. Results and potential pitfalls will be discussed in weekly group meetings. Journal clubs and seminars are scheduled on a regular basis, and the Ph.D. student will be involved in both.
You should have, or expect to hold, a 1st or 2.1 in a biological science-related undergraduate BSc degree (or equivalent), preferably a Masters in a related subject, and experience in undertaking laboratory research projects using a range of techniques.
*Please note the English Language Requirement for EU Students is an IELTS score of 6.5 with no band score lower than 5.5.
To apply please send:
• Curriculum Vitae
• Letter of intention, explaining interest and why they think they are well placed to do this
To: [Email Address Removed];
For application enquiries contact: Laura Whitty: [Email Address Removed]
Deadline: 22 June at 13.00.
Start date: 1 September or 1 October, negotiable.
Interviews on 28 June.