Kennedy Trust Prize Studentships
Novel mediators of inflammatory bowel disease
The inflammatory bowel diseases (IBDs), comprising Crohn’s Disease (CD) and ulcerative (UC) colitis, are severe inflammatory disorders of the gastrointestinal tract. They affect 2.2 million people across Europe and patients often suffer from debilitating symptoms including abdominal cramping and bloody diarrhoea. There is no current cure for the disease and treatment consists of long-term immunosuppressive therapy which poses an increased risk of potentially serious infections. Genome-wide association studies (GWAS) have helped to identify many IBD-associated loci, although only a few, including the Interleukin 23 (IL23) and IL23-Receptor (IL23R) and Interferon Regulatory Factor 5 (IRF5) are common across CD and UC.
Macrophages are abundant cells in the gut and central in sensing as well as responding to environmental alterations and are therefore important for orchestrating intestinal homeostasis. Intestinal macrophages require constant replenishment throughout adult life. This is achieved via classical monocytes infiltrating from blood and differentiating through a series of short-lived intermediaries to generate mature macrophages. We have recently shown that IRF5 controls experimentally induced colitis by regulating multiple aspects of monocyte/macrophage biology in the gut, including monocyte infiltration in to the gut, functional adaptation to the tissue environment, progression through the intermediary states and production of pro-inflammatory molecules, such as IL-12p40 subunit of IL-23. By examining the patterns of gene expression in intestinal macrophages at a single-cell level, we have mapped the heterogeneity of their states during colitis and identified novel molecular targets that appear to be under IRF5 control. These include classical complement molecule C1q, with previously reported role in phagocytosis and efferocytosis, tissue repair and fibrosis, but yet undefined function in intestinal homeostasis and inflammation.
To address the functional relevance of the identified novel pathways in initiation and resolution of intestinal inflammation, anti-microbial activity and tissue regeneration, and to dissect possible molecular mechanisms, we will use the combination of in vitro macrophage cultures and in vivo experimental models of colitis. Applying cutting edge genomic, imaging, biochemical and molecular approaches to macrophages competent in or lacking the key pathway molecules we will examine the relationship between the elements of the pathway during the course of inflammation and define points suitable for therapeutic targeting. This project is ideally suited to a student with a strong molecular immunology background and an interest in both functional genomics and cellular immunology.
- Weiss M, Byrne AJ, Blazek K, Saliba DG, Pease JD, Perocheau D, Feldmann M, Udalova IA. IRF5 controls both acute and chronic inflammation. Proceedings of the National Academy of Sciences. 2015 Sep 1;112(35):11001-6.
- Arnold IC, Mathisen S, Schulthess J, Danne C, Hegazy AN, Powrie F. CD11c(+) monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23. Mucosal Immunol. 2016 Mar;9(2):352-63.
- Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011 Jun 15;474(7351):298-306.
The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Students will be based at the Kennedy Institute of Rheumatology, where they will benefit from state-of-the-art molecular biology, flow cytometry, and microscopy infrastructure. Training will be provided in techniques in a wide range of functional genomic (single-cell and bulk RNA-Seq, ATAC-Seq, ChIP-Seq) approaches, imaging (immunofluorescence on tissue sections) and immunological (cell isolation, tissue culture, FACS, CyTOF) techniques. This project will be primarily wet-lab based, but the student will have an opportunity to develop their computational skill-set to analyse data generated from RNA-seq and CyTOF experiments. Recently developed novel in vivo models of inflammatory diseases will be extensively used. A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology and data analysis. Students will attend weekly seminars within the department and those relevant in the wider University. Students will be expected to present data regularly to the department, the Genomics of Inflammation and Mucosal Immunology laboratories and to attend external conferences to present their research globally. Students will benefit integration with a multidisciplinary team within the Oxford Biomedical Research Centre in Gastroenterology and Mucosal Immunity.
How to Apply
The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Directors of Graduate Studies who will be able to advise you of the essential requirements.
Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system.
The application guide and form is found online and the DPhil or MSc by research will commence in October 2018.
When completing the online application, please read the University Guide.
Immunology; Molecular, Cell and Systems Biology; Genes, Genetics, Epigenetics and Genomics