The role of mucosal serotonin in visceral nociception and gut motility

项目摘要/摘要 肠易激综合征(IBS)是一种以内脏疼痛和运动障碍为特征的高度流行的疾病。 肠易激综合征在儿童和成人中造成相当大的发病率，目前的治疗方法是不够的。5-羟色胺(5-HT) 信号在疼痛和运动中发挥作用，但修改5-羟色胺信号来治疗IBS的疗效有限。 充满了负面影响。进一步了解肠源性5-羟色胺在IBS病理生理学中的作用 因此可以为这种情况提供新的和有效的治疗方法。肠嗜铬细胞(EC) 胃肠道(GI)上皮产生肠道中大部分的5-羟色胺，这被认为是刺激外源性初级的 促进感觉和运动的传入神经元(EXPAN)和固有初级传入神经元(IPAN)终末 分别发信号。5-羟色胺再摄取转运体(SERT)迅速存在于上皮细胞中 使5-羟色胺失活。选择性5-羟色胺再摄取抑制剂(SSRI)抑制SERT，从而增加5-羟色胺的利用率 用于IPAN和Exan刺激。尽管SSRI用于儿科IBS，但往往无效，并受到 不良的胃肠道影响，这可能是由于它们对胃肠道上皮以外的部位的影响。我的前辈和 初步数据强烈表明，上皮性限制性5-羟色胺的调节可以限制有害的影响，从而 提高治疗水平。我的数据还显示了一种新的内脏疼痛机制，涉及SERT对粘膜5-羟色胺的调节。 太好了。在目前的方案中，我将研究上皮5-羟色胺对胃肠动力和内脏伤害性感受的影响 使用诱导或抑制EC细胞分泌的光遗传工具，缺乏粘膜5-羟色胺或 SERT，以及改变粘膜5-羟色胺信号的药物干预。建议的研究策略 将使我能够检验这样的假设：1)EC细胞释放5-羟色胺；2)SERT介导的 粘膜5-羟色胺可调节内脏伤害性感觉和胃肠动力。

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.