Intestinal 5-HT Transporter: A novel therapeutic target for GI disorders

肠道 5-HT 转运蛋白：胃肠道疾病的新型治疗靶点

基本信息

批准号：
10316170
负责人：
Ravinder K Gill
金额：
$ 45.63万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316170
关键词：
AHR gene Actinobacteria class Affect Agonist Antiinflammatory Effect Aryl Hydrocarbon Receptor Attenuated Bacteria Bifidobacterium Binding Blood flow CCL20 gene CYP11A1 gene CYP1A1 gene Candidate Disease Gene Cells Chronic Communities Complex Data Diarrhea Diet Dietary Phytochemical Disease Down-Regulation Drug Metabolic Detoxication Effectiveness Electrolytes Enteral Enterochromaffin Cells Enzymes Epithelial Cells Event Experimental Models Functional disorder Funding Gastrointestinal tract structure Gene Targeting Genes Genetic Gut Mucosa Health Homeostasis Hormones Human Ileitis Immune Immune response Immunity Impairment Infection Inflammation Inflammatory Bowel Diseases Intervention Intestinal Motility Intestines Knock-out Knockout Mice Lead Ligands Link Maintenance Mediating Microarray Analysis Modeling Molecular Mus Neurons Neurotransmitters Nuclear Receptors Oral Administration Outcome Pathogenesis Pathologic Pathway interactions Patients Physiological Processes Predisposition Probiotics Receptor Activation Receptor Signaling Resistance Role Serotonin Severities Signal Pathway Small Intestines Structure Supplementation Susceptibility Gene Therapeutic Intervention Tissue-Specific Gene Expression Transport Process Tryptophan Up-Regulation Wild Type Mouse Xenobiotic Metabolism Xenobiotics absorption antimicrobial peptide aryl hydrocarbon receptor ligand bacterial community cruciferous vegetable dietary dysbiosis efficacy evaluation extracellular gut inflammation gut microbiota ileum in vivo Model insight intestinal epithelium microbiota microbiota metabolites mouse model new therapeutic target novel novel therapeutic intervention overexpression prevent response reuptake serotonin receptor serotonin transporter uptake villin

项目摘要

Serotonin transporter (SLC6A4; SERT) represents a primary mechanism to regulate 5-HT availability in the gut mucosa. A large body of evidence supports linkage of SERT to various GI disorders, however, the mechanisms are not well understood. Our recent studies and preliminary data demonstrated an entirely novel role of SERT and intracellular 5-HT in the activation of Aryl hydrocarbon receptor (AhR), a newly recognized IBD susceptibility gene. Interestingly, SERT KO mice fed with AhR agonist (β-naphthoflavone) showed impaired induction of CYP1A1, the canonical AhR gene target. Our preliminary data further showed that SERT was essential for the maintenance of healthy gut microbiota, as deletion of SERT in mice was associated with a reduction in actinobacteria, and altered community structure that may affect the availability of ligands known to activate AhR. Since AhR pathways regulate gut immunity, the decrease in SERT may contribute to the pathophysiology of intestinal inflammation by suppressing basal and agonist-induced AhR activity. However, the mechanisms linking this novel paradigm of the role of serotonergic machinery in dysbiosis and agonist induced AhR activation are not known. Interestingly, dietary AhR ligands such as those present in cruciferous vegetables have protective roles in ameliorating intestinal inflammation. However, a decrease in SERT expression associated with inflammation may dampen their effects and reduce effectiveness in the course of IBD. We hypothesize that SERT-mediated uptake of 5-HT is crucial for the activation of AhR in response to dietary ligands. We also hypothesize that agents which activate SERT and/or counteract its down regulation will confer novel anti-inflammatory effects via AhR dependent mechanisms. Proposed studies in Specific Aim 1 will: a) investigate cell specific mechanisms by which 5-HT activates intestinal AhR utilizing mouse and human enteroids; b) examine whether loss of SERT renders resistance to the beneficial effects of dietary AhR ligands in TNBS ileitis model; and; c) elucidate the effects of microbiota in the activation of AhR pathways utilizing fecal transfer and investigate the link between SERT and the ability of microbiota to produce AhR ligands. Given that SERT is consistently shown to be decreased in all models of inflammation and patients with IBD, proposed studies in Specific Aim 2 will examine the efficacy of natural AhR ligands present in the diet in preventing the onset of gut inflammation, when combined with agents that upregulate SERT, such as probiotic Bifidobacteria breve. In addition, the role of SERT upregulation on mechanisms of AhR activation will be investigated utilizing state-of-the-art mouse model of epithelial cell- specific inducible overexpression of SERT. Outcome of the proposed studies should define the molecular mechanisms by which 5-HT activates AhR and should establish this novel link of the host serotonergic machinery with gut inflammation via AhR and gut microbiota/metabolites. These studies should also establish the beneficial role of SERT up regulation as a novel interventional strategy for IBD.

5-羟色胺转运蛋白（SLC6A4; SERT）代表调节肠道5-HT可用性的主要机制粘膜。大量证据支持SERT与各种GI疾病的联系，但是，机制尚不清楚。我们最近的研究和初步数据证明了一个完全新颖的 SERT和细胞内5-HT在芳基烃受体（AHR）激活中的作用，这是一种新认识的 IBD敏感性基因。有趣的是，以AHR激动剂（β-萘叶酮）喂养的SERT KO小鼠 CYP1A1的诱导受损，CYP1A1，规范AHR基因靶标。我们的初步数据进一步表明对于维持健康的肠道微生物群是必不可少的，因为小鼠的SERT缺失与肌细菌的降低，并改变了可能影响已知配体可用性的社区结构激活AHR。由于AHR途径调节了肠道免疫，因此SERT的减少可能有助于通过抑制碱性和激动剂诱导的AHR活性，肠道炎症的病理生理学。然而，将这种新颖的范式与血清素能机制在营养不良和激动剂中的作用联系起来的机制诱导的AHR激活尚不清楚。有趣的是，饮食中的AHR配体，例如在十字花科中存在的饮食蔬菜在改善肠道炎症中具有保护作用。但是，Sert的减少与炎症相关的表达可能会抑制其影响并降低效果 IBD。我们假设SERT介导的5-HT摄取对于AHR的激活至关重要饮食配体。我们还假设激活SERT和/或抵抗其向下的代理调节将通过AHR依赖机制介绍新型的抗炎作用。拟议的研究在特定的目标1中将：a）研究5-HT激活肠道AHR利用细胞特定机制小鼠和人类肠to b）检查SERT的损失是否会导致对有益影响的抵抗力 TNBS回肠炎模型中的饮食AHR配体；和; c）阐明微生物群在AHR激活中的影响使用粪便转移的途径，并研究SERT与微生物群产生的能力之间的联系 Ahr配体。鉴于在所有炎症模型中都始终显示SERT得到改善 IBD患者，特定目标2的拟议研究将检查天然AHR配体的效率在饮食中存在于防止肠道注射发作的饮食，与更新的代理相结合 Sert，例如益生菌双歧杆菌。另外，Sert上调在AHR机制上的作用将使用上皮细胞特异性诱导的最新小鼠模型研究激活 Sert的过表达。拟议研究的结果应通过哪个5-HT激活AHR，应与宿主血清素能机械的这种新颖链接通过AHR和肠道微生物群/代谢产物注射肠道。这些研究也应确定 Sert调节作为IBD的新型介入策略的有益作用。