Enteric glia and visceral pain

肠神经胶质细胞和内脏疼痛

• 批准号: 10112902
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112902
• 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，也是功能障碍的主要原因 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，但对于负责产生的机制仍没有达成共识 腹痛的缺乏进展体现在当前疗法的疗效不佳和停滞不前。 该提案的总体目标是了解腹痛的新型靶向疗法的进展。 使内脏神经纤维敏感的机制，该提案的具体重点是机制 肠神经胶质细胞在中枢神经系统疼痛传递的调节中发挥核心作用。 系统，但是肠道中的神经胶质细胞和神经纤维之间的相互作用如何有助于产生 内脏疼痛尚不清楚，该提议检验了肠神经胶质细胞对内脏疼痛的贡献这一中心假设。 通过与伤害感受器直接相互作用以及通过调节免疫反应间接产生超敏反应。 对偶假设将在两个具体目标中进行测试，利用靶向遗传模型来操纵神经胶质细胞， 建立内脏过敏动物模型，并进行光遗传学记录、免疫组化 化验、电生理学和内脏运动反射记录来研究对感觉神经元活动的影响 目标 1 将检验肠道神经胶质细胞直接调节内脏活动的假设。 具体目标 1a 将使用化学遗传学和基因敲除小鼠模型来研究伤害感受器的作用。 胶质递质释放和Specific Aim 1b将使用选择性药物和基因敲除小鼠来研究胶质细胞的作用 调节 ATP 和组胺可用性的胞外酶 目标 2 将检验肠神经胶质细胞的假设。 具体目标 2a 将使用通过与免疫细胞相互作用间接调节内脏伤害感受器。 转基因小鼠和单克隆抗体研究神经胶质细胞与巨噬细胞介导的相互作用 Specific Aim 2b 将使用基因敲除小鼠和单克隆抗体来释放 ATP 和 M-CSF 等介质。 研究其次依赖于神经胶质细胞和淋巴细胞之间相互作用的抗体 由抗原呈递介导的免疫反应将通过微阵列进行分析， 这项研究的结果将确定胶质细胞免疫的新作用。 这种对内脏敏感机制的新见解。 神经将促进功能性胃肠道腹痛新疗法的开发 疾病，例如 IBS 和 IBD。