Autophagy and Crohn's disease: translating genetics to function

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I aim to investigate the molecular biology of Crohn‘s disease (CD), a chronic debilitating inflammatory bowel condition affecting 100 - 250 per 100,000 people in the UK. Although current understanding suggests that an abnormal response to bacteria living in the gut leads to Crohn‘s inflammation, the mechanisms are not understood - yet understanding this mechanism might permit development of improved treatments or even preventative measures. Recent groundbreaking studies have highlighted two genes involved in autophagy as being significantly associated with CD risk. I will study one of these genes, ATG16L1. Autophagy is a cellular process that degrades unwanted large proteins and other cell structures, and is also implicated in clearance of invasive bacteria. We hypothesise that autophagy is abnormal in CD, leading to defective clearance of bowel pathogens and therefore inflammation. A series of experiments are proposed to test this hypothesis. Using established cell lines from animals and humans, and bowel samples from patients with CD, I will study the effects of the CD-associated variant in ATG16L1 on autophagy, characterize cellular components with which Atg16L1 protein interacts and investigate whether autophagy is generally abnormal in CD even without the currently identified genetic variants.