Constipation is common in the elderly and in many patients it is a significant problem that affects quality of life. Laxatives and other remedies are typically required to alleviate symptoms, however these are often less effective in the elderly and are associated with side effects that limit compliance. Current treatment for constipation involves increasing stool water and enhancing enteric nervous system mediated colonic motility. Clinical studies and work in animal models has shown that aging reduces enteric nerve density and the activity of smooth muscle signaling pathways that promote acto-myosin interactions, and hence contraction. Here we propose a chemical screen in zebrafish to identify compounds that enhance intestinal transit through direct effects on smooth muscle. These compounds are predicted to work independently of the enteric nervous system, and downstream of the signaling molecules affected by aging, thus, they have the potential to be effective pro-kinetic agents that enhance intestinal transit in elderly patients. The proposal consists of three specific aims. The goal of the first aim is to optimize and automate a zebrafish intestinal transit screening assay to identify compounds that enhance smooth muscle contractility. The goal of the second aim is to conduct a pilot screen of a library of FDA approved drugs and novel chemical compounds to gauge the performance of the intestinal transit assay in a large scale screen. The goal of the third aim is to conduct studies that will be begin to define the mechanism of action of active compounds identified in the pilot screen.
Constipation is a common problem in the elderly and has a significant impact on overall health and quality of life. Recent studies suggest that the underlyin causes of constipation differ in elderly versus young and middle aged patients. The long term goal of this project is to identify chemical compounds that can be developed into drugs with novel mechanisms of action that can be used to treat severe constipation in the elderly.