Enteric Neuronal Development as a Determinant of Intestinal Inflammation

肠道神经元发育是肠道炎症的决定因素

基本信息

批准号：
8443290
负责人：
Kara Gross Margolis
金额：
$ 15.42万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443290
关键词：
Affect American Basal lamina Cells Chronic Clinical Colitis Colon Crohn&apos s disease Data Defect Defensins Delayed Hypersensitivity Deltastab Dendritic cell activation Development Diarrhea Dinitrofluorobenzene Ear Edema Enteral Enteric Nervous System Epithelial Etiology Extravasation Flagellin Functional disorder Gene Expression Genes Genetic Models Genetically Engineered Mouse Horseradish Peroxidase Human Hyperplasia Immune Immune system Immunity Immunoblotting Immunology In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Infiltrate Inflammatory disease of the intestine Interferons Interleukin-1 Interleukin-10 Interleukin-6 Intestinal Diseases Intestinal Mucosa Intestines Investigation Irritable Bowel Syndrome Knowledge Lamina Propria Leukocyte Elastase Link Location Measurement Measures Mediating Mentors Mucous Membrane Mus Myelogenous Myenteric Plexus Natural Immunity Necrotizing Enterocolitis Nerve Nervous System Physiology Nervous system structure Neuraxis Neurons Neutrophil Infiltration Oral Pathogenesis Pathway interactions Patients Permeability Phosphotransferases Play Population Predisposing Factor Preparation Production Proteins Proteoglycan Quality of life Regulation Regulatory T-Lymphocyte Reporting Research Resistance Role Scaffolding Protein Severities Signal Transduction Small Intestines Spleen Submucous Plexus T-Lymphocyte TLR5 gene TNF gene TNFRSF5 gene Testing Tight Junctions Time Training Transcript Transgenes Trypsin Ulcerative Colitis Universities Up-Regulation Wild Type Mouse absorption career development cell motility commensal microbes cytokine design expectation fluorescein isothiocyanate dextran immunocytochemistry immunoregulation in vitro Assay in vivo innate immune function intestinal epithelium lymphocyte proliferation macromolecule neurogenesis neuron development neurophysiology occludin p65 public health relevance syndecan toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): This application is to support my career development at Columbia University under the sponsorship of Michael D. Gershon (enteric neurophysiology/development), Charalabos Pothoulakis (intestinal inflammation) and Lloyd Mayer (immunology). The training plan includes courses, mentored research, and protected research time. My investigation is designed to analyze putative contributions of the enteric nervous system (ENS) to the pathophysiology of intestinal inflammation and neuroimmune interactions in the bowel wall. Increased numbers of enteric neurons have been reported in inflamed regions of the gut in patients with inflammatory bowel disease (IBD) or intestinal neurogangliomatosis. It is impossible to determine in humans whether neuronal hyperplasia predates intestinal inflammation, results from it, or contributes to its severity. We have used, as genetic models, mice in which the ENS is hyperplastic (NSE-noggin mice) or hypoplastic (Hand2+/- mice) to test the hypothesis that ENS hyperplasia is proinflammatory. Preliminary data show that measures of severity (survival, clinical and histological scores, intestinal expression of genes encoding proinflammatory molecules, levels of neutrophil elastase and p50 NF B) of TNBS- and DSS-induced colitis are higher in NSE- noggin and lower in Hand2+/- mice than in their wild-type (WT) littermates. In neither mouse, however, are differences from WT found in measures of the severity (edema, T cell and neutrophil infiltration, and expression of IL1 , IFN , and TNF ) of delayed type hypersensitivity evoked in the ears with dinitrofluorobenzene. Transgene effects on inflammation are thus limited to the bowel. These observations are consistent with the hypotheses that ENS hyperplasia contributes to the severity of intestinal inflammation and, potentially also therefore, to the pathogenesis of IBD. I now propose to investigate mechanisms by which the ENS affects intestinal inflammation. I will determine whether the proinflammatory effects of ENS hyperplasia are due to altered (i) intestinal barrier function, (ii) innate immunity, and (iii) immunoregulation. The ability of enterc neurons to affect TLR4 and TLR5 signaling at baseline and during inflammation will be examined. I will determine the effect of the ENS on the integrity of epithelial tight junctions and basal laminae as well as bidirectional translocation of macromolecules across the intestinal epithelium. Analyses of numbers, location, and proportions of regulatory T cell (Treg) subsets (from lamina propria and spleen) as well as their ability to inhibit lymphocyte proliferation will e employed to test hypotheses that ENS hyperplasia decreases Treg number and/or function. Intestinal inflammation occurs in intestinal disorders besides IBD, including necrotizing enterocolitis, infectious diarrhea, and irritable bowel syndrome; the ENS may contribute to any or all of them. Knowledge of interactions between the ENS and inflammatory effectors, therefore, has the potential to transform understanding and, ultimately, treatment of many intestinal disorders.

描述（由申请人提供）：此申请是为了支持我在哥伦比亚大学的职业发展，该大学在迈克尔·D·格申（Michael D.培训计划包括课程，指导研究和受保护的研究时间。我的研究旨在分析肠神经系统（ENS）对肠壁中肠道炎症和神经免疫相互作用的病理生物生物生物的推定贡献。据报道，肠道疾病（IBD）或肠道神经瘤性患者的肠道区域的肠神经元数量增加。在人类中，不可能确定神经元增生是否早于肠道炎症，是由其引起的，还是导致其严重程度。我们已经使用过遗传模型，ENS是增生（NSE-NOGGIN小鼠）或降压器（手2 +/-小鼠）的小鼠，以检验ENS增生性促炎的假设。初步数据表明，严重程度（生存，临床和组织学得分，编码促炎分子的基因的肠道表达，TNBS- tNBS-诱导的结肠炎的基因，中性粒细胞弹性酶的水平和p50 nf b）和nse nse-Noggin中的nse-nse-nse-nse-nse-nse-nse-nse-nse-nse-nse-nse-nse-nse-nse-nse-nse pers persy hist2 +/-鼠标较高。然而，在这两种小鼠中，在严重程度（水肿，T细胞和中性粒细胞浸润）的测量中发现了与WT的差异，以及用二硝基氟苯在耳朵中引起的延迟类型超敏反应的IL1，IFN和TNF的表达。因此，转基因对炎症的影响仅限于肠道。这些观察结果与ENS增生有助于肠道炎症严重程度的假设一致，因此也可能与IBD的发病机理有关。我现在建议研究ENS影响肠道炎症的机制。我将确定ENS增生的促炎作用是否是由于（i）肠屏障功能改变，（ii）先天免疫和（iii）免疫调节。将检查ENTERC神经元在基线和炎症期间影响TLR4和TLR5信号传导的能力。我将确定ENS对上皮紧密连接的完整性的影响基底层薄片以及大分子跨肠上皮的双向易位。对调节T细胞（Treg）子集的数量，位置和比例的分析（来自椎板和脾脏）及其抑制淋巴细胞增殖的能力将用于测试假设，以测试ENS增生可降低TREG数量和/或功能的假设。肠道炎症发生在IBD以外的肠道疾病中，包括坏死性小肠结肠炎，感染性腹泻和肠易激综合征。 ENS可能会为其中任何一个或全部做出贡献。因此，对ENS和炎症效应子之间相互作用的知识具有改变理解并最终治疗许多肠道疾病的潜力。