How Paneth cells become a site for intestinal inflammation

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Crohn's disease (CD) affects 1 in 300 of the UK population, causing severe recurrent abdominal symptoms mainly in young adults - disrupting education, jobs and family life. Many patients require steroids, long-term immunosuppressants and antibody therapies and 75% ultimately require major surgery +/- ileostomy. The cause of Crohn's remains unknown but since 2007 there has been huge progress in understanding its genetic basis. In particular defects in a process called autophagy (a cellular pathway for the degradation and recycling of cellular components), have been highlighted in the development of ileal CD. Work pioneered by the Kaser lab has focused attention on the role of the Paneth cell and revealed these as potential originators of intestinal inflammation. Paneth cells are intestinal secretory cells that regulate the interface between the millions of bugs that live in the gut and our immune system. In a mouse model cells with the same human genetic risk for impaired autophagy become stressed in the presence of intestinal microbiota and the animals were found to develop ileal inflammation with many of the features of Crohn's disease. The key aims of this research proposal are 1. To extend our knowledge of the key inflammatory pathways that Paneth cells engage 2. Tounderstand how and which immune cells are affected downstream of this3. To identify if there are similar biomarkers allowing CD patients to be stratified based on this disease mechanismThis research will be undertaken in the Kaser laboratory at Addenbrooke's Hospital in Cambridge. Using the mouse model described above Paneth cells will be isolated to study what inflammatory mechanisms are engaged that result activation of specific immune cells and ultimately in ileal inflammation. Following this, human biopsies from patients with CD and similar genetic impairment will be investigated to see if these observations are recapitulated.The research will be conducted by Dr Joya Bhattacharyya, a specialist registrar in gastroenterology who has taken time out of clinical training to undertake research training and pursue a PhD. The overarching theme of this research proposal is to use a mouse model to gain mechanistic insight into the cause of Crohn's disease, thereby allowing us to understand how genetic risk factors result in intestinal inflammation. This line of research may ultimately identify specific biomarkers that can be used to target therapies towards those patients most likely to benefit from them.