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Intestinal Immunology: exploring disease associated colonic mesenchymal populations, investigating molecular determinants of their evolution and function in barrier breakdown in IBD

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  • Full or part time
    Prof A Simmons
    Dr H Koohy
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

We study how the intestinal immune system functions to enable the symbiotic relationship with the intestinal microflora required for health. We are interested in how that relationship breaks down leading to inflammatory bowel disease.

Inflammatory bowel disease affects 1 in 250 people and has been difficult to treat in some patients as little is known of the cellular make up of tissue lesions observed in different manifestations of this disease. We have used single cell technologies to create an unbiased map of single mucosal cell types present in the human or murine intestine. Applying this approach to epithelial cells enabled us to define trajectories of secretory or absorptive cells that undergo extensive remodelling in inflammatory bowel disease (IBD). A similar analysis of mesenchymal cells allowed us to define several new cell states including the colonic crypt niche cell that directs epithelial stem cell function in health. Pathological remodelling of the mesenchyme in IBD revealed pathways driving immune infiltration and impairing epithelial reconstitution in this disease (1). In current work, we are using a similar unbiased approach to define how immune cells remodel and interact with both intestinal epithelia and mesenchyme in differing forms of IBD. We will study the effect of IBD susceptibility genes (2, 3) on these processes. Dominant pathological features of IBD associated immune infiltrates are being interrogated using genetic models in vitro and in vivo. In tandem, we examine what molecular features of the enteric microflora might contribute to breakdown of immunoregulation in IBD, building on our experience documenting enteric host pathogen interactions (4, 5).

A PhD project is available to explore disease associated colonic mesenchymal populations, investigating molecular determinants of their evolution and function in barrier breakdown in IBD.

Students will based in the MRC Human Immunology Unit (HIU), MRC Weatherall Institute of Molecular Medicine (WIMM), a world-renowned research centre focused on defining mechanisms of disease. Students will have access to state of the art facilities and training in a broad range of techniques. Projects involve use of single-cell RNA-sequencing, single-cell ATAC-sequencing, FACS, CyTOF, confocal microscopy, CRISPR/Cas9 genetic manipulation, super-resolution microscopy, proteomic and metabolomic analysis. Some work involves use of advanced cell culture techniques including or populations of rare intestinal mucosal cells. Microbiological skills such as bacterial culture, gene targeting and sequencing may be employed. Training in computational biology and analysis of single-cell or microbial datasets will be provided as required. Our work is supported by collaborations with many scientists locally and internationally.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework.

Funding Notes

Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.

Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.

References

Kinchen J, Chen HH, Parikh K, Antanaviciute A, Jagielowicz M, Fawkner-Corbett D, Ashley N, Cubitt L, Mellado-Gomez E, Attar M, Sharma E, Wills Q, Bowden R, Richter FC, Ahern D, Puri KD, Henault J, Gervais F, Koohy H, Simmons A. (2018). Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease. Cell. 2018 Oct 4;175(2):372-386.e17. PMID: 30270042

Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A (2010). NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Medicine Jan;16(1):90-7. PMID: 19966812

Brain O, Owens BM, Pichulik T, Allan P, Khatamzas E, Leslie A, Steevels T, Sharma S, Mayer A, Catuneanu A M, Morton V, Sun M Y, Jewell D, Coccia M, Harrison O, Maloy K, Schönefeldt S, Bornschein S, Liston A, Simmons A. (2013). The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity Sep 19;39(3):521-36. PMID: 24054330.

Aulicino A, Rue-Albrecht KC, Preciado-Llanes L, Napolitani G, Ashley N, Cribbs A, Koth J, Lagerholm CB, Ambrose T, Gordon MA, Sims D and Simmons A. Invasive Salmonella Exploits Divergent Immune Evasion Strategies in Infected and Bystander Dendritic Cell Subsets. Accepted, Nature Communications, 2018.

Khatamzas E, Hipp MM, Gaughan D, Pichulik T, Leslie A, Fernandes RA, Muraro D, Booth S, Zausmer K, Sun MY, Kessler B, Rowland-Jones S, Cerundolo V, Simmons A. (2017). Snapin promotes HIV-1 transmission from dendritic cells by dampening TLR8 signaling. EMBO J. 36(20):2998-3011. PMID: 28923824

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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