Sex, serotonin and visceral hypersensitivity

性、血清素和内脏过敏

• 批准号: 8970701
• 负责人: James J. Galligan
• 金额: $ 33.42万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970701
• 关键词: Acute; Affect; Afferent Neurons; Animal Model; Bacteria; Cations; Cavia; Chronic; Colon; Colorectal; Corticotropin-Releasing Hormone; Data; Electrophysiology (science); Estradiol; Estrogens; Exposure to; Female; Functional disorder; GPER gene; Gastrointestinal Motility; Genes; Genetic Polymorphism; Gonadal Steroid Hormones; Granisetron; Harvest; Health; Hypersensitivity; In Vitro; Individual; Irritable Bowel Syndrome; Knock-out; Lactobacillus reuteri; Libraries; Measures; Messenger RNA; Modeling; Mutate; Neurons; Nociception; Pain; Pain Disorder; Patients; Peristalsis; Pharmaceutical Preparations; Pharmacology; Physiology; Preparation; Principal Investigator; Probiotics; Promoter Regions; Property; Rattus; Sensation Disorders; Serotonin; Serotonin Receptors 5-HT-3; Severities; Signal Transduction; Specificity; Spinal; Spinal Ganglia; Spinal cord posterior horn; Stress; Study models; Symptoms; Testing; United States; Visceral; Visceral Afferent Neuron; Visceral pain; Whole-Cell Recordings; Woman; afferent nerve; antagonist G; antalarmin; effective therapy; gastrointestinal; in vivo; male; men; motility disorder; mutant; nerve supply; neurotransmission; novel; novel therapeutics; programs; receptor; response; serotonin receptor; serotonin transporter; sex; tissue culture

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a gastrointestinal motility and visceral sensation disorder that affects 30 million people in the United States. IBS is twice as common in women as men and IBS symptom severity is related to fluctuations in circulating female sex hormones and to episodes of stress. In addition, drugs which act at some 5-hydroxytryptamine (5- HT serotonin) receptors relieve IBS symptoms, including visceral pain, in some patients. Finally, many IBS patients have a polymorphism in the promoter region of the gene that encodes the serotonin transporter (SERT). This polymorphism leads to low SERT expression. These data indicate that there is an interaction between serotonin and female sex hormone signaling that leads to IBS symptoms especially visceral pain. The underlying pathophysiology of visceral pain is unclear and this is partly due to a lack of animal models where mechanistic and interventional studies can be conducted. We will use This hypothesis will be tested using male and female serotonin transporter (SERT) knockout (KO) rats, which we propose is an animal model of sex specific visceral hypersensitivity. This project will test th hypothesis that 5-hydroxytryptamine (5-HT, serotonin) corticotropin releasing hormone (CRH) and estrogen signaling interact to increase neurotransmission of primary afferent neurons supplying the colon to second order spinal sensory neurons and that probiotic bacteria L. reuteri (Lactobacillus reuteri 6475) can be used as a safe and effective treatment for visceral pain in IBS. The overall hypothesis will be tested in 3 specific aims. Specific aim 1 will tes the hypothesis that 5-HT3 and CRH1 antagonists can reduce visceral hypersensitivity as measured by the visceromotor response (VMR) to colorectal balloon distention (CRD). Specific aim 2 will test the hypothesis that the probiotic bacteria L. retueri can reduce visceral hypersensitivity in female SERT KO rats and this this probiotic may be a safe and effective treatment for visceral pain in IBS. Specific aim 3 will test the hypothesis that serotonin, 17-beta estradiol and CRH interaction to alter the excitability of colon projecting sensory neurons and that colon projecting neurons from female SERT KO rats will show reduced excitability. The data would indicate that the SERT KO rat is a model for studying changes in the sensory nerve supply of the gut that leads to visceral hypersensitivity.

描述（由申请人提供）：肠易激综合征（IBS）是一种胃肠道运动和内脏感觉障碍，在美国影响着3000万人。IBS在女性中的发病率是男性的两倍，IBS症状的严重程度与循环女性性激素的波动和压力发作有关。此外，作用于某些5-羟色胺（5- HT - 5-羟色胺）受体的药物可缓解肠易激综合征症状，包括一些患者的内脏疼痛。最后，许多肠易激综合征患者在编码血清素转运体（SERT）的基因启动子区域存在多态性。这种多态性导致SERT的低表达。这些数据表明，血清素和女性性激素信号之间存在相互作用，导致肠易激综合征症状，尤其是内脏疼痛。内脏疼痛的潜在病理生理学尚不清楚，部分原因是缺乏可以进行机制和介入性研究的动物模型。我们将使用雄性和雌性血清素转运体（SERT）敲除（KO）大鼠来验证这一假设，我们提出这是一种性别特异性内脏过敏的动物模型。本项目将验证5-羟色胺（5-HT， 5-羟色胺）促肾上腺皮质激素释放激素（CRH）和雌激素信号相互作用，增加供应结肠的初级传入神经元向二级脊髓感觉神经元的神经传递，以及益生菌L. reuteri （Lactobacillus reuteri 6475）可作为肠易激综合征内脏疼痛的安全有效治疗的假设。整个假设将在三个具体目标中进行检验。特异性目的1将验证5-HT3和CRH1拮抗剂可以通过对结肠直肠球囊膨胀（CRD）的内脏运动反应（VMR）来降低内脏超敏反应的假设。具体目标2将验证益生菌乳杆菌可以减少雌性SERT KO大鼠内脏过敏的假设，这种益生菌可能是一种安全有效的治疗肠易激综合征内脏疼痛的方法。具体目标3将测试血清素，17- β