Study of Advanced GastroIntestinal Therapy through Tissue biomARkers in Ulcerative colitiS (SAGITTARIUS)
- Project No: NCKIR11
- Intake: 2022 KIR Clinical
Ulcerative colitis (UC) represents a spectrum of heterogeneous diseases for which new treatments are urgently needed. Individual variability in relapse frequency, complications of disease and treatment response drives significant variability in the impact on quality of life and level of disability from UC. There currently exist multiple treatment options including immunosuppressants, immunomodulators and advanced/biologic therapies. Despite the efficacy of multiple classes of available advanced therapies, subsets of patients do not initially respond and/or become resistant to therapy. Previous work has identified associations with therapy non-response in inflammatory bowel disease, including IL-1 driven stromal-neutrophil interactions, or high levels of expression of oncostatin M and the oncostatin M receptor in inflamed colon [1,2].
In this study, we propose to apply cutting edge biological techniques to 1) study the postulated mechanism of action of UC therapies at a molecular level, 2) assess whether select populations of cell types or associated gene expression could predict therapy response, 3) and use relevant disease models and functional studies to further validate any relevant gene modules or cell-cell interactions. This will aid in striving towards better patient stratification and the discovery of novel therapeutic targets.
This is a longitudinal observational study embedded within standard-of-care therapy. The successful candidate will be required to recruit participants and collect human samples through engagement with the local inflammatory bowel disease service. The postholder must have relevant clinical training including full registration with the General Medical Council and significant experience working within the NHS (including within Gastroenterology). Further, the study is expected to generate vast bioinformatic data at a single cell level. The appointed candidate is therefore expected to have previous experience in the use of statistical software such as R or Python, and postgraduate training at MSc level or equivalent in a relevant field (e.g., medical statistics or health data science).
Ulcerative colitis, advanced therapy, transcriptomics, human biopsies, precision medicine
The successful candidate will be embedded within the Arthritis-Therapy Acceleration Programme (A-TAP) at the Kennedy Institute of Rheumatology (KIR), Oxford. The KIR is a world-leading centre in the fields of tissue biology, inflammation, and repair, with a strong emphasis on clinical translation. They will receive supervision and training by an experienced team of clinician scientists interested in the cell biology of inflammatory bowel disease. They will work closely with collaborators in the John Radcliffe Hospital and the Wellcome Trust Centre for Human Genetics.
Specific training opportunities/benefits include:
- Patient recruitment, histopathology, single-cell RNA-sequencing analysis, and other cutting-edge cell biology techniques available in-house.
- Strong translational environment as part of this Industry partnership
- Well-established DPhil programme with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists
- Highly collaborative environment with expertise ranging from molecular and cell biology to in vivo models and computational biology / genomics analysis.
- Friedrich M, et al. IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med 2021;27:1970–1981.
- West N, Hegazy A, Owens B, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease. Nat Med 2017;23:579–589.
- Uzzan M, Martin JC, Mesin L et al. Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nat Med 2022;28:766–779.
- Lamb CA, Saifuddin A, Powell N, Rieder F. The Future of Precision Medicine to Predict Outcomes and Control Tissue Remodeling in Inflammatory Bowel Disease. Gastroenterology 2022;162(5):1525-1542.
Inflammatory bowel disease