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Understand the genetics of inflammatory bowel disease using single-cell data


Project Description

The gastrointestinal tract is a complex ecosystem that has co-evolved with trillions of commensal microbes. Our intestinal microbial communities play a fundamental role in host health and training of the immune system, yet when maladapted can lead to chronic inflammatory diseases such as inflammatory bowel disease (IBD)1. Dysbiosis characterized by altered microbiota composition has been linked to IBD, cancer, and arthritis among other disorders. Currently, a bottleneck in microbiome research is to move beyond descriptive correlations and define the molecular underpinnings of host-microbial cross-talk. To address this, we are now performing gnotobiotic studies in our new state-of-the-art germ-free animal facility to identify causal mechanisms by which specific microbes modulate health and disease.

In this project, students will combine cutting edge experimental approaches with bioinformatic analyses to interrogate the reciprocal relationship between the host and microbiota. Microbial induction of IL10 is a critical feature of immune tolerance, and we have recently identified a polysaccharide produced by Helicobacter hepaticus that induces IL10 and an anti-inflammatory gene signature in macrophages2. In the context of IL10 deficiency however, H. hepaticus drives intestinal inflammation and the development of colitis is associated with functional shifts in the microbiome3. By utilizing a microbiota model community, this work will uncover pathobionts with pro-inflammatory potential as well as beneficial microbes that promote tolerance. How these microbial factors influence host responses can be probed using methodologies encompassing genetic models, reporter strains, and identifying commensal-reactive T cells4-6. Working closely with colleagues in the laboratory, metatranscriptomic and metabolomic profiles of this model community will reveal microbial signals that modulate host health. Ultimately, this research will uncover fundamental insights into the maintenance of intestinal homeostasis and accelerate the development of new therapeutic strategies in chronic inflammatory diseases.

TRAINING OPPORTUNITIES

Students will be based at the Kennedy Institute of Rheumatology (KIR), a world-renowned research centre housing state-of-the-art technologies in microbiome research, functional genomics, high-resolution immune profiling, and imaging modalities. Students will also benefit from integration and technology transfer within the University of Oxford Translational Gastroenterology Unit and Inflammatory Arthritis Microbiome Consortium. The Powrie Lab possesses unique anaerobic culturing capabilities to isolate microbiota strains, and students will learn to cultivate and manipulate model communities. The KIR houses one of the few germ-free animal facilities within the United Kingdom, and training will include germ-free studies and colonization with specific microbes in gnotobiotic experiments. This multidisciplinary project will also include training to characterize immune responses and cellular networks with well-established tools in the lab. Bioinformatics training will be provided to characterize microbial communities, with additional opportunities to develop computational skills analysing complex data sets generated in the lab (IgA-SEQ, RNAseq).

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including immunology, genetics, musculoskeletal biology, data analysis, and translational medicine. Students will attend journal club and weekly seminars within the department, as well as those relevant in the wider University. Work-in-progress will be presented regularly in Powrie lab meetings and to the department. There will also be opportunities to attend external conferences and to present research globally.

Funding Notes

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 2019.

References

Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011 Jun 15;474(7351):298-306.

Danne C, Ryzhakov G, Martinez-Lopez M, Ilott NE, Franchini F, Cuskin F, Lowe EC, Bullers SJ, Arthur JSC, Powrie F. 2017. A large polysaccharide produced by Helicobacter hepaticus induces an anti-inflammatory gene signature in macrophages. Cell Host Microbe. 2017 Dec 13;22(6):733-745.e5.

Ilott NE, Bollrath J, Danne C, Schiering C, Shale M, Adelmann K, Krausgruber T, Heger A, Sims D, Powrie F. Defining the microbial transcriptional response to colitis through integrated host and microbiome profiling. ISME J.2016 Oct;10(10):2389-404.

Hegazy AN, West NR, Stubbington MJT, Wendt E, Suijker KIM, Datsi A, This S, Danne C, Campion S, Duncan SH, Owens BMJ, Uhlig HH, McMichael A, Oxford IBD Cohort Investigators, Bergthaler A, Teichmann SA, Keshav S, Powrie F. Circulating and tissue-resident CD4+ T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation. Gastroenterology. 2017 Nov;153(5):1320-1337.e16.

Krausgruber T, Schiering C, Adelmann K, Harrison OJ, Chomka A, Pearson C, Ahern PP, Shale M, Oukka M, Powrie F. T-bet is a key modulator of IL-23-driven pathogenic CD4(+) T cell responses in the intestine. Nat Commun.2016 May 19;7:11627.

Schiering C, Krausgruber T, Chomka A, Fröhlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN, Harrison OJ, Owens BMJ, Löhning M, Belkaid Y, Fallon PG, Powrie F. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature.2014 Sep 25;513(7519):564-568.

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