Linking Myosin 5b and Intestinal Alkaline Phosphatase in Intestinal Inflammation - Project Summary/Abstract Inflammatory bowel disease (IBD) has emerged as a substantial health concern not only in the developed world but also in developing countries. The incidence of IBD is increasing on a global scale, highlighting its significance as a growing health issue. The exact cause of IBD remains unclear, but it is postulated to result from a combination of genetic, environmental, and immunological/microbial factors. Preliminary data suggests that Myosin 5b may play a role in the pathogenesis of inflammation in the gastrointestinal tract. Myosin 5b is a molecular motor that regulates intracellular trafficking of diverse cargo in intestinal epithelial cells. Among its many functions, Myosin 5b transports essential proteins to the apical membrane in the intestine. Loss of Myosin 5b in experimental models and in humans results in shortened microvilli which normally line the intestinal epithelial cells. In healthy individuals, microvilli act as a barrier to harmful luminal contents and bacteria. An important function of intestinal microvilli is the generation of luminal vesicles from the tips of microvilli that contain catalytically active enzymes. Intestinal alkaline phosphatase (IAP) is enriched in microvilli derived vesicles and in microvilli. IAP removes phosphate groups from bacterial lipopolysaccharide and flagellin. Dephosphorylation of bacterial products by IAP dampens the release of pro-inflammatory signals thereby protecting the intestinal epithelium. This research proposal aims to investigate the interplay between pro-inflammatory stimuli and the expression of Myosin 5b in the setting of IBD. We hypothesize decreased Myosin 5b results in decreased trafficking of IAP to microvilli. This disruption compromises the function of microvilli at the apical membrane, ultimately leading to increased inflammation. The proposed study will employ a multidisciplinary approach, leveraging our lab’s expertise in gastrointestinal epithelial cell biology, intracellular trafficking, advanced microscopy, animal models and physiology. We will use both in vitro and in vivo models to dissect the relationship between Myosin 5b and IAP in intestinal inflammation. This proposal will provide a better understanding of the function of Myosin 5b in the distal intestine and the impact of alterations in Myosin 5b on gut homeostasis and inflammation. Results from this study will provide experimental evidence of inflammation resulting from decreased intestinal Myosin 5b and its effect on microvilli function.
