Role of Myosin 5b in Maintaining the Epithelial Integrity of the Colon

Medical University Of South Carolina, Charleston SC

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Abstract

Research Project 1 - 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 progressively 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 is enriched in microvilli derived vesicles and in microvilli. Intestinal alkaline phosphatase removes phosphate groups from bacterial lipopolysaccharide and flagellin. Dephosphorylation of bacterial products by intestinal alkaline phosphatase dampens the release of pro- inflammatory signals thereby protecting the intestinal epithelium. This research proposal aims to investigate the link between Myosin 5b and intestinal alkaline phosphatase in intestinal inflammation. We hypothesize that decreased levels of Myosin 5b result in decreased trafficking of intestinal alkaline phosphatase to microvilli. This disruption compromises the function of microvilli at the apical membrane, ultimately leading to a perpetuating cycle of intestinal 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. Additionally, the use of MUSC core resources and mentoring provided by the COBRE in Digestive & Liver Disease will ensure accomplishment of the proposed studies and the success of Dr. A Engevik’s lab. We will use both in vitro and in vivo models to dissect the two aspects of this project: (1) the requirement of functional Myosin 5b to limit inflammatory responses, and (2) examination of epithelial cytokine levels in the setting of non-functional Myosin 5b. This proposal highlights the need for a better understanding of the function of Myosin 5b in the distal intestine and the impact of alterations in Myosin 5b in gut homeostasis and during inflammation. Results from this study will serve as the foundation of future R01 applications.