Regulation of excitability and propulsive contraction in the colon

结肠兴奋性和推进性收缩的调节

• 批准号: 8742139
• 负责人: SANG Don KOH
• 金额: $ 19.04万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742139
• 关键词: Anus; Automobile Driving; Cells; Colon; Comparative Study; Complex; Constipation; Coupled; Data; Defect; Dependence; Development; Disease; Distal; Employee Strikes; Enteral; Enteric Nervous System; Event; Gastrointestinal Motility; Generations; Healthcare; Human; Instruction; Interstitial Cell of Cajal; Intestinal Motility; Investigation; Migrating Myoelectric Complex; Monkeys; Motor; Motor Neurons; Movement; Mus; Muscarinic Antagonists; Muscle; Nerve; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase; Oral; Organ; Output; Pathway interactions; Patients; Pattern; Peptides; Peristalsis; Phase; Physiological; Platelet-Derived Growth Factor; Publishing; Records; Reflex action; Regulation; Relaxation; Reporter; Response to stimulus physiology; Role; Signal Pathway; Signal Transduction; Simulate; Site; Smooth Muscle Myocytes; Source; Specificity; Sphincter; Stimulus; Transgenic Mice; base; cell motility; cell population study; excitatory neuron; gastrointestinal; inhibitory neuron; interstitial cell; migration; neurotransmission; nonhuman primate; novel; purinoceptor P2Y1; receptor; research study; response

Gastrointestinal (Gl) motility patterns depend, in part, on coordination of contractile activity by enteric motor neurons. Enteric excitatory and inhibitory motor neurons contribute to development of appropriate motor patterns in Gl organs. In the colon a prominent motor pattern, known as colonic migrating motor complexes (CMMC) provides propulsive forces for movement of fecal material in the anal direction. At present CMMC are thought to be based on the peristaltic reflex in which local stimuli generate ascending contractions and descending inhibition. This concept has become canonical in neurogastroenterology. In fact there is a 3rd phase of the peristaltic reflex that is poorly understood and infrequently even mentioned in scholariy reviews of peristalsis. Enteric motor neurons activate excitatory and inhibitory neurons and elicit region-dependent contraction and relaxation responses. In most regions of the gut, including the colon, the response to nerve stimulation is followed by a post-stimulus excitatory response (PSR also known as rebound excitation). We have discovered that PSR is actually an extremely important component, if not the main propulsive force, in propagating contractions (i.e. CMMC). CMMC are reduced by only an extent by muscarinic antagonists and not dependent upon excitatory peptides. CMMC are totally eliminated by inhibition of nitric oxide synthase in proximal colon or P2Y1 receptors in distal colon. Thus, CMMC are not dependent upon migrating responses to excitatory nerves but on migrating inhibitory responses coupled to PSR. There are striking similarities in PSR between species, and such a high degree of conservation tends to indicate the importance of PSR in colonic motility. Modifying canons, like the peristaltic reflex, requires careful investigation and determination of the mechanisms driving PSR. Our experiments will reveal the cell-specific steps and signaling pathways responsible for PSR and these findings will provide remarkable new ideas about managing colonic propulsive disorders. We will use reporter strains of transgenic mice for cell studies of PSR, and comparative studies on colonic muscles and whole colonic segments from mice, non-human primates, and human patients to develop a unified and mechanistic concept of PSR and its importance in propulsive movements. RELEVANCE (See instructions): Slow transit constipation is a prevalent health care problem that has been assoicated with loss of interstitial cells of Cajal. In this project we will explore the role of ICC in generating propulsive contraction in the colon and show the consequences of a defect in these cells for nrormal colonic transit.

胃肠（GI）运动模式部分取决于肠道运动对收缩活动的协调 神经元肠兴奋性和抑制性运动神经元有助于适当运动的发育 GI器官的模式。在结肠中有一个突出的运动模式，称为结肠移行运动复合体 （CMMC）为粪便物质在肛门方向上的移动提供推进力。目前，CMMC 被认为是基于蠕动反射，其中局部刺激产生上行收缩， 下行抑制这一概念已成为神经胃肠病学的规范。事实上，有第三个 蠕动反射的一个阶段，这是了解甚少，甚至很少提到的学术评论 - 是的肠运动神经元激活兴奋性和抑制性神经元， 收缩和舒张反应。在肠道的大部分区域，包括结肠， 刺激之后是刺激后兴奋性反应（PSR，也称为反弹兴奋）。我们 我发现PSR实际上是一个非常重要的组成部分，如果不是主要的推进力， 传播收缩（即CMMC）。CMMC仅在一定程度上被毒蕈碱拮抗剂降低， 不依赖于兴奋肽。CMMC完全消除抑制一氧化氮合酶， 近端结肠或远端结肠的P2 Y1受体。因此，CMMC并不依赖于对 兴奋性神经，但迁移抑制反应耦合到PSR。PSR中有惊人的相似之处 这种高度的保守性倾向于表明PSR在结肠癌中的重要性。 能动性修改大炮，像蠕动反射，需要仔细的调查和确定的， 驱动PSR的机制。我们的实验将揭示细胞特异性步骤和信号通路 负责PSR，这些发现将为管理结肠推进提供显着的新思路 紊乱我们将使用转基因小鼠的报告品系进行PSR的细胞研究，并对 来自小鼠、非人灵长类动物和人类患者的结肠肌肉和整个结肠段， 一个统一的和机械的概念PSR及其在推进运动中的重要性。 相关性（参见说明）： 慢传输型便秘是一种普遍存在的健康问题，其与间质性 Cajal细胞在这个项目中，我们将探讨ICC在结肠产生推进收缩中的作用， 显示了这些细胞缺陷对正常结肠运输的影响。