Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.687920
Title: Use of transgenic mice to study the role of autophagy protein ATG16L1 in Crohn's disease
Author: Betts, Meghan
ISNI:       0000 0004 5915 9729
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2016
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Abstract:
Crohn’s disease (CD) is a chronic inflammatory bowel disorder that primarily affects the ileum and colon. CD aetiology is complex, with the current most widely accepted hypothesis being that disease onset is triggered by environmental factors that alter the intestinal microbiota and abnormally stimulate the intestinal immune response in genetically susceptible individuals. Genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP) conferring T300A in the autophagy gene ATG16L1 as a CD susceptibility locus1. ATG16L1 is an essential component of the autophagy pathway, a conserved cellular degradation pathway also linked to bacterial defence2. It is not known how disruptions in ATG16L1 or autophagy contribute to CD pathogenesis, although evidence increasingly suggests their involvement in defective defence against bacterial infections. We hypothesise that autophagy defects caused by mutations in ATG16L1 prevent effective clearance of pathogens and/or pathobionts by xenophagy, resulting in a persistent infection and overt inflammation. To address this question we generated and characterised mice with an intestinal epithelial cell (IEC)-targeted deletion of Atg16L1 (Atg16L1ΔIEC) and validated our findings by histological analysis of intestinal tissue from CD patients expressing the CDrisk variant of ATG16L1 (*300A). To determine whether a combination of Atg16L1 mutations and a bacterial infection leads to the development of CD-like pathogenesis, Atg16L1ΔIEC mice were characterised following infection with Salmonella Typhimurium. We confirm that Atg16L1 is required for autophagy and show that an IEC-targeted deletion of this gene without an additional bacterial challenge does not initiate intestinal inflammation. Following S. Typhimurium infection, Atg16L1ΔIEC mice exhibited an enlargement of colonic goblet cells. In contrast, CD patients expressing *300A displayed smaller colonic goblet cells. Infected Atg16L1ΔIEC mice also exhibited colonic crypt atrophy and a reduced number of ileal villi; however there was no evidence of increased inflammation either prior to- or post- infection with S. Typhimurium. Trends of increased bacterial dissemination to peripheral organs were also observed in Atg16L1ΔIEC mice, suggesting that Atg16L1 is essential for regulating IEC xenophagy and is required to prevent systemic infection of mice with S. Typhimurium.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.687920  DOI: Not available
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