Neuronal Excitability and Motility in Colitis

结肠炎中的神经元兴奋性和运动性

• 批准号: 7204560
• 负责人: Gary M Mawe
• 金额: $ 28.04万
• 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/7204560
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：肠壁中的神经元控制肠道对摄入的食物的反应;它们还调节消化，营养吸收和废物清除的过程。在炎症性肠病（IBD）中，肠道功能的各种特征，包括运动性，分泌和敏感性都发生了改变。由于肠道的神经细胞调节所有这些功能，这些神经元的变化可能会导致导致患者经历痛苦的症状。在过去的3年中，我们已经评估了炎症诱导的变化沿着电路的结肠在逐步的方式，我们已经确定了基本的变化，特别是在三个网站：（1）增加5-羟色胺在粘膜层的可用性;（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，这些变化如何影响结肠运动，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测试假设，即内在感觉神经元过度兴奋涉及下调中间电导，Ca 2+激活的K* 通道和上调超极化激活的阳离子通道。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肌间神经丛中突触前神经递质释放、突触后敏感性和神经末梢密度的变化来研究突触易化的机制。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，以确定反射回路中哪些炎症诱导的变化导致结肠运动改变以及这种情况是如何发生的。在具体目标4中，我们将测试炎症诱导的神经可塑性和运动性的相关变化是否持续到从炎症中恢复之后。这些变化是标准诊断程序无法检测到的，并且可能是炎症性肠病缓解期间和炎症后肠易激综合征（IBS）中肠道功能改变的基础。将使用一系列技术，包括细胞内电压和电流记录，真实的时间定量聚合酶链反应，电子显微镜，和数字增强运动分析。通过这种方式，我们将提供一个独特的，综合/翻译的观点，在发炎的结肠神经传递。这些研究的结果，所有这些都是高度可行的，将提高我们对炎症结肠的病理生理学的理解，他们将提高我们对IBS的理解。