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）：肠壁上的神经元控制肠道对摄入餐的反应；他们还调节消化，营养吸收和废物消除过程。在炎症性肠病（IBD）中，肠道功能的各种特征，包括运动，分泌和敏感性。由于肠道的神经细胞调节了所有这些功能，因此这些神经元的变化可能导致症状导致受苦的个体所经历的痛苦。在过去的三年中，我们以逐步的方式评估了炎症诱导的沿结肠回路的变化，并且我们尤其确定了三个地点的基本变化：（1）粘膜层中血清素的可用性增加； （2）固有的感觉神经元过度刺激性； （3）神经元之间的突触信号促进。所提出的实验旨在阐明这些变化的基础的机制，这些变化如何影响结肠运动以及在炎症中恢复后的变化持续存在。在特定目标1中，我们将使用电生理学和分子方法来检验以下假设：固有的感觉神经元过度兴奋性涉及中间电导，Ca2+激活的K*通道以及超极化激活阳离子阳离子阳离子通道的上调。在特定的目标2中，我们将使用电生理学和电子显微镜来研究突触促进的机制，通过测试突触前神经递质释放，突触后灵敏度和神经终末密度的变化。在特定的目标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有助于结肠运动的改变以及如何发生。在特定目标4中，我们将测试炎症引起的神经可塑性和运动性的相关变化是否持续超出炎症的恢复。标准诊断程序将无法检测到这种变化，并且在炎症性肠病和炎性后炎症后肠综合征（IBS）中的缓解过程中可能会改变肠道功能。将使用一系列技术，包括细胞内电压和当前记录，实时定量聚合酶链反应，电子显微镜和数字增强的运动性测定。这样，我们将在发炎的结肠中提供神经传递的独特，综合/翻译视图。这些研究的发现，所有这些都非常可行，将增强我们对发炎结肠的病理生理学的理解，它们将提高我们对IBS的理解。