Regulation of enteric motor neurocircuits by enteric glia in health and disease

健康和疾病中肠神经胶质细胞对肠运动神经回路的调节

• 批准号: 10213012
• 负责人: BRIAN D. GULBRANSEN
• 金额: $ 34.51万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10213012
• 关键词: Acute; Address; Affect; Biological Assay; Cells; Chronic; Colitis; Complex; Cues; Data; Development; Disease; Enteral; Enteric Nervous System; Feedback; Functional disorder; Funding; Gastrointestinal Diseases; Gastrointestinal Motility; Glial Fibrillary Acidic Protein; Goals; Health; Human; Image; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Motility; Intestinal Pseudo-Obstruction; Intestines; Irritable Bowel Syndrome; Knockout Mice; Mediator of activation protein; Modeling; Motor; Motor Pathways; Mus; Muscle; Mutant Strains Mice; Neural Pathways; Neuroglia; Neuronal Plasticity; Neurons; Neurotransmitters; Nitrergic Neurons; Peristalsis; Pharmaceutical Preparations; Phase; Recruitment Activity; Reflex action; Regulation; Role; Signal Transduction; Specificity; Synapses; System; Testing; Tissues; Transgenic Mice; calcium indicator; cell motility; excitatory neuron; experimental study; gastrointestinal; glial activation; inhibitory neuron; insight; motility disorder; motor behavior; mouse model; neural circuit; neural network; neuroinflammation; neuron loss; neuronal excitability; neuroregulation; neurotransmission; novel; novel strategies; novel therapeutics; recruit; therapeutic development

PROJECT SUMMARY Reflexive motor behaviors of the intestine including peristalsis are controlled by the enteric nervous system (ENS); a complex neural network embedded in the gut wall. Perturbations within the ENS contribute to the development of dysmotility in irritable bowel syndrome, inflammatory bowel disease, and severe motility disorders such as chronic intestinal pseudo-obstruction, but the mechanisms responsible for persistent changes in enteric neural circuitry are unknown. Recent data show that enteric glia, non-neuronal cells that surround enteric neurons, regulate neuronal excitability and contribute to neuroinflammation. The overall goal of this proposal is to define how specialized interactions between enteric glia and neurons regulate motility and how alterations in those mechanisms contribute to disease. This proposal tests the central hypothesis that enteric glia are specialized to potentiate the activity of ascending excitatory neural pathways involved in normal contractile motility, and that disruption of this regulatory system by inflammation contributes to neuronal hyperexcitability. This dual hypothesis will be tested in two specific aims that utilize genetically encoded calcium indicators to study neuron-glia interactions, glial chemogenetic actuators to study how glia modulate specific types of enteric neurons, and a post-inflammatory model of enteric neuroplasticity to study how glia contribute to neuronal hyperexcitability following inflammation. Aim 1 will test the hypothesis that enteric glia are specialized to sense excitatory neurons and potentiate ascending neural pathways involved in the contractile phase of motility. Aim 1.1 will use genetically encoded calcium indicators to study glial recruitment by polarized neural pathways in motility reflexes. Aim 1.2 will combine the chemogenetic activation of enteric glia with neuronal and glial imaging using genetically encoded calcium indicators to test the hypothesis that glia differentially affect subsets of enteric neurons. Aim 2 will test the hypothesis that glia contribute to neuronal hyperexcitability following colitis by increasing positive feedback to excitatory neurons and by reducing inhibitory feedback from inhibitory neurons. Aim 2.1 will study how altered interactions between glia and excitatory neurons contribute to neuronal hyperexcitability following colitis. Aim 2.2 will use mutant mice and selective drugs to study how glia contribute to neuronal hyperexcitability through interactions with inhibitory neurons. The results of this study will provide novel insight into glial mechanisms that regulate the excitability of enteric neural circuits. A better understanding of the glial mechanisms that regulate motility will facilitate the development of therapeutics for dysmotility by revealing novel targets to modify gastrointestinal reflexes.

项目总结 肠道的反射运动行为，包括蠕动，是由肠道神经系统控制的。 (ENS)；嵌入肠壁的复杂神经网络。神经内窥镜内的扰动导致了 肠易激综合征、炎症性肠病和严重肠动力障碍的发展 慢性假性肠梗阻等疾病，但其致病机制持久 肠神经回路的变化是未知的。最近的数据显示，肠神经胶质细胞，非神经细胞， 包围肠道神经元，调节神经元的兴奋性，促进神经炎症。总目标 这一建议的目的是定义肠神经胶质细胞和神经元之间的特殊相互作用如何调节运动性和 这些机制的改变如何导致疾病。这一提议检验了核心假设，即 肠神经胶质细胞专用于增强正常神经通路中上行兴奋性神经通路的活性。 收缩运动，炎症破坏这一调节系统有助于神经元 过度兴奋。这一双重假设将在两个特定的目标上进行检验，这两个目标利用遗传编码 钙指示剂用于研究神经元与胶质细胞的相互作用，神经胶质化学发生促进剂用于研究神经胶质细胞如何调节 特定类型的肠神经细胞，以及炎症后肠神经可塑性模型来研究胶质细胞是如何 有助于炎症后的神经元过度兴奋。目标1将检验肠道神经胶质细胞 专门用于感觉兴奋性神经元并增强参与 运动的收缩阶段。AIM 1.1将使用遗传编码的钙指示剂来研究神经胶质细胞的招募 通过运动反射中的极化神经通路。AIM 1.2将结合肠道的化学生成激活 使用基因编码的钙指示剂进行神经和神经胶质成像来检验胶质细胞的假说 不同程度地影响肠道神经元的亚群。目标2将检验胶质细胞对神经元有贡献的假设 结肠炎后通过增加兴奋性神经元的正反馈和通过减少 抑制性神经元的抑制性反馈。AIM 2.1将研究胶质细胞和神经胶质之间的相互作用如何改变 兴奋性神经元有助于结肠炎后神经元的过度兴奋性。AIM 2.2将使用突变小鼠和 选择性药物研究神经胶质细胞如何通过与抑制性物质的相互作用促进神经元的过度兴奋 神经元。这项研究的结果将为调节兴奋性的神经胶质机制提供新的见解。 肠道神经回路。更好地了解调节运动性的神经胶质机制将有助于 通过揭示改变胃肠道反射的新靶点来开发运动障碍的治疗方法。