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.
Functional GI diseases, hallmarked by irritable bowel syndrome (IBS), are estimated to affect ~15% of the US population. The chronic nature of IBS leads to a high amount of healthcare consumption and productivity loss, which both lead to expenses estimated at $20 billion per year. IBS is a complex multiorgan disease with a poorly understood pathophysiology. This leads to poorly effective symptom-targeted treatments with many side effects. We know that mechanosensation is disrupted in a large proportion of patients with IBS. The work in this proposal aims to understand the mechanosensitivity of a novel GI circuit we call gut touch. This novel approach to studying gut mechanosensitivity may provide a fresh view of the mechanisms of gut function in health and lead to novel targeted treatments. This work has substantial public health relevance, since the results of these studies will yield novel diagnostic and therapeutic targets to move IBS treatments from being based on symptoms to those that are based on disease mechanism.
