Impact of Gut Epithelial Serotonin on Afferent Neuron Function and Visceral Pain Signaling

PROJECT SUMMARY/ABSTRACT Visceral pain is a debilitating symptom of irritable bowel syndrome (IBS), a highly prevalent disorder that impacts >11% of people worldwide. Visceral pain results from increased excitation of extrinsic primary afferent neurons (ExPANs) that project from the intestinal tract to the spinal cord. Clinical and experimental evidence suggest that IBS-related pain is caused, at least in part, by dysregulation of serotonin (5-HT), a key regulator of ExPAN sensitivity; however, current strategies to modify 5-HT signaling as a pain therapy have limited efficacy and significant adverse effects. To determine how 5-HT can be better targeted for visceral pain treatment, the proposed studies focus on the impact of gut epithelium-derived 5-HT on ExPAN function. Enterochromaffin (EC) cells of the epithelium produce most of the 5-HT in the gut, which stimulates ExPANs to promote sensory signaling. The serotonin reuptake transporter (SERT), present throughout the gut epithelium, rapidly inactivates 5-HT. My preliminary data strongly suggest that epithelial-restricted 5-HT modulation is a promising target for pain therapy that would limit adverse effects. With the support of a K01 Mentored Research Scientist Development Award, this proposal will define how epithelial 5-HT impacts ExPAN signaling to produce pro- or anti-nociceptive effects. I will accomplish this in two specific aims, with mentored training in electrophysiology, single cell molecular analysis, and biophysical assays to assess 5-HT receptor trafficking. Aim 1: How does gut epithelial 5-HT regulate ExPAN activation? I will determine how availability of epithelial 5-HT impacts ExPAN mechanosensitivity and excitability, which are neuronal properties that directly influence pain perception. Aim 2: Does gut epithelial 5-HT regulate expression and function of ExPAN 5-HT receptors? I will determine how increased epithelial 5-HT affects 5-HTR signaling and trafficking in ExPANs, which will have the potential to reveal intracellular targets for visceral pain treatment. My mentoring team and I have designed this proposal to provide me with the necessary research training and professional development to establish an independent academic career in the fields of neurogastroenterology and pain signaling.