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Determining the role of adherent-invasive E. coli in Crohn’s disease – cause or consequence? (SCHULLERMEDOCT2020)


Project Description

Crohn’s disease is a type of inflammatory bowel disease which affects at least 120,000 people in the UK. It is a lifelong condition often diagnosed in young adulthood. Symptoms include diarrhoea, abdominal pain and weight loss, and complications such as bowel obstruction and cancer can occur. There is currently no cure, and treatments are based on anti-inflammatory and immunosuppressive drugs. The causes for Crohn’s disease remain unknown, but research suggests a combination of genetic and environmental factors resulting in a leaky gut epithelium, defects in bacterial clearance and an over-reactive immune response. Previous studies have demonstrated a prevalence of adherent-invasive Escherichia coli (AIEC) in Crohn’s tissues with bacteria invading the intestinal epithelium. At present, it remains unclear if AIEC are a cause or consequence of Crohn’s disease due to a lack of suitable experimental model systems.

In this PhD project, we will determine the role of AIEC in Crohn’s disease by 1) establishing human intestinal stem cell-derived organoids from tissues of Crohn’s patients and healthy controls, 2) investigating intrinsic differences in epithelial permeability and antimicrobial defence in Crohn’s versus control organoids, and 3) evaluating epithelial susceptibility to AIEC infection (intracellular replication, autophagy and phagocytosis). Results from this study will elucidate how AIEC contribute to the development of Crohn’s disease which will aid the design of improved treatment strategies and evaluation of potential drug candidates for Crohn’s.

The successful PhD student will receive expert training in human intestinal organoid culture, work with bacterial pathogens, cell and molecular biology, immunochemistry and bioimaging by members of the Schüller and Wileman groups at UEA. They will collaborate with Dr Chan at the Quadram Institute Endoscopy Facility who will provide human tissue.

More information on the supervisor for this project: https://people.uea.ac.uk/s_schuller
Type of programme: PhD
Start date: October 2020
Mode of study: Full-time
Studentship length: 3 years

Entry requirements;
Acceptable first degree in Biological and Biomedical Sciences, the standard minimum entry requirement is 2:1

Funding Notes

This PhD project is in a Faculty of Medicine and Health Sciences competition for funded studentships. These studentships are funded for 3 years and comprise of Home/EU fees, a stipend of £15,009 and £1000 per annum to support research training.Overseas applicants may apply but are required to fund the difference between home/EU and overseas tuition fees (in 2020-21 the international fee is £19,100 for lab based projects and £15,700 for non-lab based projects but fees are subject to an annual increase).

References

1. Hews CL, Tran SL, Wegmann U, Brett B, Walsham AD, Kavanaugh D, Ward NJ, Juge N, and Schüller S (2017) The StcE metalloprotease of enterohaemorrhagic Escherichia coli reduces the inner mucus layer and promotes adherence to human colonic epithelium ex vivo. Cell Microbiol 19: e12717.
2. Ellis SJ, Yasir M, Browning DF, Busby SJW, Schüller S (2019) Oxygen and contact with human intestinal epithelium independently stimulate virulence gene expression in enteroaggregative Escherichia coli. Cell Microbiol 23: e13012.
3. Rai S, Arasteh J, Jefferson M, Pearson T, Wang Y, Zhang W, Bicsak B, Divekar D, Powell P, Naumann R, Beraza N, Carding S, Florey O, Mayer U, Wileman T (2019) The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3 associated phagocytosis. Autophagy 15: 599-612.
4. Fletcher K, Ulferts R, Jacquin E, Veith T, Gammoh N, Arasteh JM, Mayer U, Carding S, Wileman T, Beale R, Florey O (2018) The WD40 domain of ATG16L1 is required for its non‐canonical role in lipidation of LC3 at single membranes. EMBO J 37: e97840.
5. Khalili H, Håkansson N, Chan SS, Chen Y, Lochhead P, Ludvigsson JF, Chan AT, Hart AR, Olén O, Wolk A (2020) Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn's disease: results from two large prospective cohort studies. Gut, pii: gutjnl-2019-319505. doi: 10.1136/gutjnl-2019-319505.

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