Neuronal Excitability and Motility in Colitis

结肠炎中的神经元兴奋性和运动性

• 批准号: 7351782
• 负责人: Gary M Mawe
• 金额: $ 27.48万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-12 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7351782
• 关键词: Action Potentials; Affect; Afferent Neurons; Animals; Biological Assay; Budgets; Calcium-Activated Potassium Channel; Cations; Cells; Colitis; Colon; Comprehension; Condition; Diagnostic Procedure; Digestion; Disease; Disease remission; Down-Regulation; Electron Microscopy; Electrophysiology (science); Elements; Excitatory Postsynaptic Potentials; Exhibits; Exposure to; Fire - disasters; Functional disorder; Genus Cola; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interstitial Cell of Cajal; Intestines; Investigation; Irritable Bowel Syndrome; Lead; Maps; Mediating; Mediator of activation protein; Messenger RNA; Molecular; Motor; Myenteric Plexus; Nerve; Neuronal Plasticity; Neurons; Neurotransmitters; Normal tissue morphology; Numbers; Nutrient; Pattern; Peristalsis; Polymerase Chain Reaction; Presynaptic Terminals; Process; Rate; Recovery; Reflex action; Research Personnel; Resolution; Rest; Serotonin; Signal Transduction; Site; Smooth Muscle; Standards of Weights and Measures; Stimulus; Symptoms; Synapses; Synaptic Potentials; Synaptic Transmission; Techniques; Testing; Time; Tissues; Transcriptional Activation; Up-Regulation; Week; absorption; cell motility; density; design; experience; gastrointestinal symptom; hyperpolarization-activated cation channel; improved; motility disorder; neural circuit; neuronal excitability; neurotransmission; neurotransmitter release; postsynaptic; presynaptic; programs; relating to nervous system; research study; response; spatiotemporal; voltage; wasting

Neurons in the wall of the intestine control how the gut reacts to an ingested meal; they also regulate the processes of digestion, nutrient absorption, and waste elimination. In inflammatory bowel disease (IBD), various features of gut function, including motility, secretion and sensitivity are altered. As nerve cells of the bowel regulate all of these functions, it is likely that changes in these neurons cause the symptoms that lead to the suffering experienced by afflicted individuals. In the past 3 years, we have evaluated inflammation- induced changes along the circuitry of the colon in a step-wise fashion, and we have identified fundamental changes at three sites in particular: (1) increased serotonin availability in the mucosal layer; (2) intrinsic sensory neuron hyperexcitability; and (3) facilitation of synaptic signals between neurons. The proposed experiments are designed to elucidate the mechanisms that underlie these changes, how these changes affect colonic motility, and what changes persist following recovery from inflammation. In specific aim 1, we will use electrophysiology and molecular approaches to test the hypothesis that intrinsic sensory neuron hyperexcitability involves down-regulation of intermediate conductance, Ca2+-activated K* channels and an up-regulation of hyperpolarization-activated cation channels. In specific aim 2, we will use electrophysiology and electron microscopy to investigate the mechanisms of synaptic facilitation by testing for changes in presynaptic neurotransmitter release, postsynaptic sensitivity and nerve terminal density in the myenteric plexus. In specific aim 3, we will study colonic peristalsis, spatiotemporal motility patterns and neuromuscular responses to determine which inflammation-induced changes in the reflex circuitry contribute to altered colonic motility and how this occurs. In specific aim 4, we will test whether inflammation-induced neuroplasticity and related changes in motility persist beyond recovery from inflammation. Such changes would be undetectable by standard diagnostic procedures, and could underlie altered gut function during remission from inflammatory bowel disease and in post-inflammatory irritable bowel syndrome (IBS). An array of techniques will be used, including intracellular voltage and current recordings, real time quantitative polymerase chain reaction, electron microscopy, and digitally enhanced motility assays. In this way, we will provide a unique, integrated/translational view of neurotransmission in the inflamed colon. The findings of these investigations, all of which are highly feasible, will enhance our understanding of the pathophysiology of the inflamed colon, and they will improve our comprehension of IBS.

肠壁中的神经元控制肠道对摄入食物的反应。他们还监管 消化、营养吸收和废物排除的过程。在炎症性肠病（IBD）中， 肠道功能的各种特征，包括运动性、分泌性和敏感性都发生了改变。作为神经细胞 肠道调节所有这些功能，这些神经元的变化很可能导致导致的症状 以及受苦受难的人所经历的痛苦。在过去的3年里，我们评估了炎症- 以逐步的方式引起沿结肠回路的变化，并且我们已经确定了基本的 特别是三个部位的变化：（1）粘膜层中血清素的可用性增加； (2)内在的 感觉神经元过度兴奋； (3)促进神经元之间的突触信号。拟议的 实验旨在阐明这些变化背后的机制，这些变化是如何发生的 影响结肠运动，以及炎症恢复后持续存在哪些变化。在具体目标 1 中，我们 将使用电生理学和分子方法来检验内在感觉神经元的假设 过度兴奋涉及中间电导、Ca2+激活的 K* 通道和 超极化激活的阳离子通道的上调。在具体目标 2 中，我们将使用电生理学 和电子显微镜通过测试突触促进的变化来研究突触促进的机制 突触前神经递质释放、突触后敏感性和肌间神经末梢密度 神经丛。在具体目标 3 中，我们将研究结肠蠕动、时空运动模式和 神经肌肉反应以确定哪些炎症引起的反射回路变化起作用 改变结肠运动及其发生方式。在具体目标 4 中，我们将测试炎症是否诱发 神经可塑性和相关的运动变化在炎症恢复后仍然持续存在。这样的改变 标准诊断程序无法检测到，并且可能是肠道功能改变的基础 炎症性肠病和炎症后肠易激综合征（IBS）的缓解。一个 将使用一系列技术，包括细胞内电压和电流记录、实时定量 聚合酶链反应、电子显微镜和数字增强动力测定。这样，我们将 提供发炎结肠神经传递的独特、整合/转化视图。调查结果 这些研究都非常可行，将增强我们对病理生理学的理解 发炎的结肠，它们将提高我们对 IBS 的理解。