Our laboratory?s overall goal is to determine the cellular and molecular mechanisms of gastrointestinal (GI) mechanosensitivity in normal GI physiology and in functional GI diseases, such as irritable bowel syndrome (IBS). Our K08-supported research focused on an important specialized epithelial mechanosensory cell, called enterochromaffin (EC) cell. In response to mechanical force, the EC cell releases serotonin, which has important physiologic effects and this mechanism, is disrupted in IBS. With K08 support, we discovered that a novel mechanosensitive ion channel Piezo2 is specifically expressed in mouse and human EC cells, and that Piezo2 activation leads to release of 5-HT and mechanically-induced epithelial secretion. The current work is aimed at understanding the molecular mechanism of EC cell mechanosensitivity downstream of Piezo2 channels. The experiments, while foundationally linked to previous work, are a new and logical extension of the work associated with the K08 and can be completed in the defined award period. The results from this study are important because they will define a novel mechanotransduction mechanism and allow us to deeply understand EC cell mechanosensation in health, which will enable us to examine alterations in disease, and then potentially target these pharmacologically as novel and specific therapies for IBS.
Irritable bowel syndrome (IBS) is a common condition, affecting ~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 condition that is currently poorly understood. Thus, treatments focus on symptoms, and therefore, are they are both ineffective and have significant side effects. The enterochromaffin cells are important sensory cells in the gut lining that produce and secrete serotonin. Importantly, serotonin signaling is disrupted in IBS, so understanding the enterochromaffin cell function in health is important to determine how they are affected in disease, which may enable disease- focused therapies in IBS. Mechanical forces are a strong signal for enterochromaffin cell activation. We recently discovered that a specific mechanical transducer is involved in enterochromaffin cell mechanosensitivity and this work will focus on determining the precise cellular mechanism of enterochromaffin cell mechanosensitivity. 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.