Kumagai, Tomoko; (2023) An investigation of the role of ADAM-like Decysin 1 in intestinal mucosal inflammation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

ADAM-like decysin 1 (ADAMDEC1) is a highly conserved metalloprotease which is exclusively expressed in the gastrointestinal (GI) tract, under healthy state, in various mammalian species including human. The physiological function and catalytical substrate of ADAMDEC1 remain unknown. However, a reduction in its normally high expression is seen within the tissue of GI inflammatory diseases and cancer, such as inflammatory bowel disease and colorectal cancer, which suggests that ADAMDEC1 is likely to play a vital role in physiology and potentially pathogenesis of GI diseases. Previous studies utilising dextran sodium sulfate (DSS) colitis model in Adamdec1 knockout (Adamdec1-/-) mice demonstrated an exaggerated mucosal inflammation during experimental colitis in these mice, thus the protective role of ADAMDEC1 in mucosal inflammation. However, the mechanism through which ADAMDEC1 mediates such a role in inflammation remains unknown. This project primarily aimed to characterise the role of ADAMDEC1 during intestinal mucosal inflammation. By utilising DSS-colitis model, the components of mucosal defence and immune response in which ADAMDEC1 might potentially be involved to mediate its protective role were narrowed down to: antigen presenting cell - T cell interaction, monocyte to macrophage differentiation, phenotype of monocytes and macrophages, polarisation of Th17 and Treg cells, susceptibility of epithelial cells to DSS, and inhibitory effect of ADAMDEC1 on bacterial enzymes. Furthermore, analysis of the gut microbiome of the Adamdec1-/- and WT mice revealed that ADAMDEC1’s role in mucosal inflammation was unlikely to be mediated via interaction with the microbiome. Finally, the marked impact of the environment on the gut microbiome and its impact on the expressivity of genotype were demonstrated. In conclusion, an advance was made in defining the potential role of ADAMDEC1 during mucosal inflammation. The project also demonstrated important challenges relating to environmental control when designing experiments to examine the phenotype of transgenic animals.

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