The role of mucosal serotonin in visceral nociception and gut motility

粘膜血清素在内脏伤害感受和肠道蠕动中的作用

• 批准号: 10535862
• 负责人: Sarah Najjar
• 金额: $ 6.76万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2025-09-06
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535862
• 关键词: Abdominal Pain; Ablation; Adult; Adverse effects; Afferent Neurons; Anabolism; Biological Assay; Cell secretion; Chemicals; Child; Childhood; Colon; Communication; Constipation; Cre driver; Data; Diarrhea; Disease; Enteral; Enteric Nervous System; Enterochromaffin Cells; Enzymes; Epithelial; Epithelial Cells; Functional disorder; Gastrointestinal Motility; Gastrointestinal Transit; Gastrointestinal tract structure; Intervention; Irritable Bowel Syndrome; Lead; Location; Measurement; Mediating; Migrating Myoelectric Complex; Morbidity - disease rate; Motor; Mucous Membrane; Mus; Nerve; Neuraxis; Neurons; Nociception; Pain; Persons; Pharmacology; Physiological; Play; Reflex action; Regulation; Research; Role; Selective Serotonin Reuptake Inhibitor; Sensory; Serotonin; Signal Transduction; Site; Spinal; Symptoms; Techniques; Testing; Transgenic Mice; Tryptophan 5-monooxygenase; Visceral; Visceral pain; behavior measurement; cell motility; colorectal distension; cost; effective therapy; experimental study; gastrointestinal; gastrointestinal epithelium; improved; in vivo; intervention effect; intestinal epithelium; mechanical stimulus; motility disorder; novel; optogenetics; paracrine; response; reuptake; sensor; serotonin receptor; spatiotemporal; tool

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.

项目摘要/摘要 肠易激综合征（IBS）是一种高度普遍的疾病，其特征是内脏疼痛和运动障碍。 IBS引起儿童和成人的大量发病率，目前的治疗不足。 5-羟色胺（5-HT） 信号传导在疼痛和运动中起作用，但是修改5-HT信号以治疗IB的功效是有限的，并且 充满不利影响。对肠5-HT如何促进IBS病理生理学的更多了解 因此，可以为这种情况提供新颖有效的治疗方法。肠球毒蛋白（EC）细胞 胃肠道（GI）上皮产生肠道中的大部分5-HT，被认为刺激外部原发性 传入神经元（EXPAN）和固有的初级传入神经元（IPAN）终端，以促进感觉和运动 信号分别。血清素再摄取转运蛋白转运蛋白（SERT）存在于上皮细胞中，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和扩展刺激。尽管它们用于儿科IBS，但SSRI通常却无效，并且困扰 不利的胃肠道效应，这可能是由于它们在胃肠道上皮以外的其他位点的作用。我的先前和 初步数据强烈表明，上皮限制的5-HT调制可能会限制不良影响，因此 改善治疗。我的数据还显示了一种新颖的内脏疼痛机制，涉及粘膜的SERT调节5- HT。在当前的建议中，我将研究上皮5-HT对GI运动性和内脏伤害感受的影响 使用诱导或抑制EC细胞分泌的光遗传学工具，缺乏粘膜5-HT或 SERT和药理学干预措施会改变粘膜5-HT信号传导。拟议的研究策略 我将允许我检验1）从EC细胞释放的5-HT和2）SERT介导的调节的假设 粘膜5-HT可用性调节内脏伤害感和胃肠道运动。