PROJECT SUMMARY/ABSTRACT: My laboratory's overall goal is to develop novel diagnostic and therapeutic approaches for functional GI diseases, such as irritable bowel syndrome (IBS). We focus on cellular and molecular mechanisms of gastrointestinal (GI) mechanosensitivity because mechanosensitivity is abnormal in a large fraction of these patients. Our current work is focused on an important gut epithelial cell, called enterochromaffin (EC) cell, which is responsible for production of most of the body's serotonin. We recently discovered that a mechanosensitive ion channel Piezo2 is specifically expressed in mouse and human EC cells, and that Piezo2 activation is necessary for release of 5-HT and mechanically-induced epithelial secretion. The work in this proposal is an important leap from the EC cell toward understanding of the mechanosensory circuit that these cells are involved in which we call gut touch. The experiments described here will address each of the circuit components first separately, then reconstructed circuit in the dish, and finally in vivo, in mouse and zebrafish. This work is novel both technically and intellectually and will allow us to examine GI physiology from a completely different angle. We are poised to deeply understand gut touch in health, which will enable us to examine alterations in disease, and then potentially target these pharmacologically as novel and specific therapies for IBS.