The role of mucosal serotonin in visceral nociception and gut motility

项目总结/摘要 肠易激综合征（IBS）是一种以内脏疼痛和动力障碍为特征的高度流行的疾病。 IBS导致儿童和成人的大量发病率，目前的治疗是不够的。5-羟色胺 信号传导在疼痛和运动中起作用，但修饰5-HT信号传导以治疗IBS的功效有限， 充满了负面影响更深入地了解肠道5-HT如何促进IBS病理生理学 因此可以为该病症提供新的和有效的治疗。肠嗜铬（EC）细胞在 胃肠道（GI）上皮细胞在肠道中产生大部分5-HT，这被认为是刺激外源性原发性 传入神经元（ExPAN）和内源性初级传入神经元（IPAN）末梢，以促进感觉和运动 信号，分别。5-羟色胺再摄取转运蛋白（SERT），存在于整个上皮细胞，迅速 灭活5-HT。选择性5-羟色胺再摄取抑制剂（SSRIs）抑制SERT，从而增加5-HT的可用性 用于IPAN和ExPAN刺激。尽管SSRIs用于儿科IBS，但它们通常无效，并受到以下因素的困扰： 胃肠道不良反应，这可能是由于其对胃肠道上皮以外部位的影响。我的副院长和 初步数据强烈提示，上皮限制性5-HT调节可能限制不必要的作用， 改善治疗。我的数据还显示了一种新的内脏疼痛机制，涉及SERT调节粘膜5- HT。在本研究中，我将研究上皮细胞5-HT对胃肠道运动和内脏伤害性感受的影响 使用诱导或抑制EC细胞分泌的光遗传学工具， SERT和改变粘膜5-HT信号传导的药理学干预。拟议的研究战略 将允许我测试假设，1）5-HT从EC细胞释放和2）SERT介导的调节， 粘膜5-HT可用性调节内脏伤害感受和GI运动。

PROJECT SUMMARY/ABSTRACT Irritable bowel syndrome (IBS) is a highly prevalent disorder characterized by visceral pain and dysmotility. IBS causes substantial morbidity in children and adults and current therapy is inadequate. Serotonin (5-HT) signaling plays roles in pain and motility, but the efficacy of modifying 5-HT signaling to treat IBS is limited and fraught with adverse effects. A greater understanding of how enteric 5-HT contributes to IBS pathophysiology may therefore provide for novel and effective treatments for the condition. Enterochromaffin (EC) cells in the gastrointestinal (GI) epithelium produce most of the 5-HT in the gut, which is thought to stimulate extrinsic primary afferent neuron (ExPAN) and intrinsic primary afferent neuron (IPAN) terminals to promote sensory and motor signaling, respectively. The serotonin reuptake transporter (SERT), present throughout epithelial cells, rapidly inactivates 5-HT. Selective serotonin reuptake inhibitors (SSRIs) inhibit SERT and thus increase 5-HT availability for IPAN and ExPAN stimulation. Despite their use for pediatric IBS, SSRIs are often ineffective and plagued by adverse GI effects, which may be due to their effects at sites other than the GI epithelium. My prior and preliminary data strongly suggest that epithelial-restricted 5-HT modulation may limit unwanted effects and thus improve therapy. My data also show a novel visceral pain mechanism involving SERT regulation of mucosal 5- HT. In the current proposal, I will investigate the effects of epithelial 5-HT on GI motility and visceral nociception using optogenetic tools that induce or inhibit EC cell secretion, mouse lines that either lack mucosal 5-HT or SERT, and pharmacological interventions that alter mucosal 5-HT signaling. The proposed research strategy will allow me to test the hypotheses that 1) 5-HT released from EC cells and 2) SERT-mediated regulation of mucosal 5-HT availability modulate visceral nociception and GI motility.