Enteric glia and visceral pain

肠神经胶质细胞和内脏疼痛

• 批准号: 10361567
• 负责人: BRIAN D. GULBRANSEN
• 金额: $ 40.37万
• 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: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361567
• 关键词: Abdominal Pain; Acute; Affect; Afferent Neurons; Animal Model; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Biological Assay; Cells; Communication; Consensus; Data; Development; Disease; Electrophysiology (science); Enteral; Enzymes; Extracellular Signal Regulated Kinases; Flow Cytometry; Functional Gastrointestinal Disorders; Functional disorder; Gastrointestinal tract structure; General Population; Generations; Genetic Models; Goals; Health; Histamine; Hypersensitivity; Immune; Immune response; Immune system; Immunohistochemistry; Impairment; Individual; Inflammation; Inflammatory Bowel Diseases; Instruction; Intestines; Irritable Bowel Syndrome; Knockout Mice; Link; Lymphocyte; Macrophage Colony-Stimulating Factor; Maintenance; Measures; Mediating; Mediator of activation protein; Methods; Microarray Analysis; Modeling; Monoclonal Antibodies; Nerve; Nerve Fibers; Nervous system structure; Neuraxis; Neuroglia; Neurons; Nociception; Nociceptors; Office Visits; Pain; Pathway interactions; Peripheral Nerves; Pharmaceutical Preparations; Play; Process; Reflex action; Regulation; Role; Signal Transduction; Spinal Ganglia; Stress; Testing; Transgenic Mice; Visceral; Visceral pain; Water; chronic pain; colorectal distension; gastrointestinal; immunoregulation; insight; macrophage; mouse model; neuroinflammation; novel; novel therapeutics; optogenetics; recruit; targeted treatment; therapeutic development; transmission process

ABSTRACT Abdominal pain is the most common gastrointestinal issue and is a major cause of suffering in functional gastrointestinal disorder such as irritable bowel syndrome (IBS) and in the inflammatory bowel diseases (IBD). Despite extensive efforts, there is still no consensus regarding the mechanisms responsible for producing abdominal pain. This lack of progress is reflected by the poor efficacy of current therapies and the stalled progress toward novel, targeted therapies for abdominal pain. The overall goal of this proposal is to understand mechanisms that sensitize visceral nerve fibers and the specific focus of this proposal is on mechanisms regulated by enteric glia. Glia play a central role in the regulation of pain transmission in the central nervous system, but how interactions between glia and nerve fibers in the intestine contribute to the generation of visceral pain is unknown. This proposal tests the central hypothesis that enteric glia contribute to visceral hypersensitivity by direct interactions with nociceptors, and indirectly by modulating immune responses. This dual hypothesis will be tested in two specific aims that utilize targeted genetic models to manipulate glia, established animal models of visceral hypersensitivity, and optogenetic recordings, immunohistochemical assays, electrophysiology, and visceromotor reflex recordings to study the impact on sensory neuron activity in health and disease. Aim 1 will test the hypothesis that enteric glia directly modulate the activity of visceral nociceptors. Specific Aim 1a will use chemogenetic and knockout mouse models to study the role of gliotransmitter release and Specific Aim 1b will use selective drugs and knockout mice to study the role of glial ectoenzymes that regulate ATP and histamine availability. Aim 2 will test the hypothesis that enteric glia indirectly modulate visceral nociceptors through interactions with immune cells. Specific Aim 2a will use transgenic mice and monoclonal antibodies to study glial interactions with macrophages mediated by the release of mediators including ATP and M-CSF. Specific Aim 2b will use knockout mice and monoclonal antibodies to study interactions that are secondarily dependent on interactions between glia and lymphocytes mediated by antigen presentation. Immune responses in Aim 2 will be analyzed by microarrays, immunohistochemistry, and flow cytometry. The results of this study will identify novel effects of glial–immune interactions on sensory neurons in the periphery. This new insight into mechanisms that sensitize visceral nerves will facilitate the development of new therapies for abdominal pain in functional gastrointestinal disorders, such as IBS and IBD.

抽象的 腹痛是最常见的胃肠道问题，是功能性痛苦的主要原因 胃肠道疾病，例如肠易激综合征（IBS）和炎症性肠病（IBD）。 尽管做出了广泛的努力，但仍未达成共识 腹痛。当前疗法的效率较差和停滞不前的效率不足，这种进步的不足反映了 朝着腹痛的新颖，有针对性的疗法迈进。该提议的总体目标是了解 感知内脏纤维的机制和该提案的具体重点是机制 由肠神经胶质细胞调节。神经胶质在调节中枢神经的疼痛传播中起着核心作用 系统，但是肠道中神经胶质与神经纤维之间的相互作用如何有助于产生 内脏疼痛是未知的。该提案检验了肠神经胶质有助于内脏的中心假设 通过直接与伤害感受器进行直接相互作用，并通过调节免疫反应间接相互作用。这 双重假设将以两个特定的目的进行测试，这些特定目的利用靶向遗传模型来操纵神经胶质， 内脏超敏反应和光遗传学，免疫组织化学的既定动物模型 测定，电生理学和内脏反射记录，以研究对感觉神经元活性的影响 健康与疾病。 AIM 1将检验肠神经胶质直接调节内脏活性的假设 伤害感受器。特定的目标1A将使用化学生成和基因敲除小鼠模型来研究 Gliotransmitter释放和特定AIM 1B将使用选择性药物和敲除小鼠研究神经胶质的作用 调节ATP和组胺可用性的外染料酶。 AIM 2将检验促进神经胶质的假设 通过与免疫细胞相互作用，间接调节内脏伤害感受器。特定目标2a将使用 转基因小鼠和单克隆抗体研究神经胶质相互作用与由巨噬细胞介导的巨噬细胞 释放包括ATP和M-CSF在内的介体的释放。特定的目标2B将使用淘汰小鼠和单克隆 研究二次相互作用的抗体取决于胶质细胞之间的相互作用 由抗原表现介导。 AIM 2中的免疫反应将通过微阵列分析， 免疫组织化学和流式细胞仪。这项研究的结果将确定神经胶质 - 免疫的新作用 外周中感觉神经元的相互作用。这种对内脏的机制的新见解 神经将支持发育新疗法，以胃肠道功能性胃痛 疾病，例如IBS和IBD。