Nociceptor neuron regulation of gastrointestinal barrier protection and host defense

伤害感受器神经元对胃肠道屏障保护和宿主防御的调节

• 批准号: 10530684
• 负责人: Isaac Ming-Cheng Chiu
• 金额: $ 55.61万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530684
• 关键词: Ablation; Afferent Neurons; Autoimmune Diseases; Bacteria; Calcitonin Gene-Related Peptide; Capsaicin; Cell physiology; Cells; Cellular biology; Central Nervous System; Citrobacter; Citrobacter rodentium; Data; Disease; Enteral; Epithelial Cells; Epithelium; Functional disorder; Gastroenterology; Gastrointestinal Diseases; Gastrointestinal tract structure; Genetic; Goblet Cells; Homeostasis; Host Defense; Immune; Immune response; Immunity; Immunology; Infection; Inflammation; Inflammatory; Intestines; Invaded; Lead; Ligands; M cell; Maintenance; Mammals; Maps; Mediating; Mediator; Microbe; Molecular; Mucous body substance; Mus; Nervous System; Neurobiology; Neurons; Neuropeptides; Nociception; Nociceptors; Pain; Pathogenicity; Peptide Signal Sequences; Peripheral; Peripheral Nerves; Peyer' s Patches; Physiology; Play; Population; Production; RAMP1; Reflex action; Regulation; Role; Salmonella; Salmonella typhimurium; Signal Transduction; Stimulus; T-Lymphocyte; Testing; Tissues; designer receptors exclusively activated by designer drugs; dietary; enteric pathogen; experimental study; gain of function; gastrointestinal; gastrointestinal epithelium; gut microbiota; innovation; insight; interdisciplinary approach; loss of function; microbial; molecular phenotype; mustard oil; neural; neuroimmunology; neurotransmission; novel; novel strategies; pain sensation; pathogen; receptor; villin

PROJECT SUMMARY Nociceptor neurons are peripheral sensory neurons that densely innervate the gastrointestinal tract, detecting noxious/harmful stimuli to mediate protective neural reflexes including pain. However, the role of nociceptor neurons or their molecular mediators in regulating gut physiology, barrier protection, and host defense is not well understood. Here we hypothesize that specific gut-innervating nociceptors signal to epithelial cells to modulate gut barrier defenses at homeostasis and during bacterial invasion. Our preliminary data show that nociceptor neurons and the nociceptor neuropeptide calcitonin gene-related peptide (CGRP) signal to intestinal goblet cells and microfold (M) cells, two types of gut epithelial cells that mediate barrier protection and host defenses. Recent molecular phenotyping of DRG neurons show that multiple types of nociceptors innervate the gut. In this project, we will utilize targeted genetic and molecular approaches to: 1) Determine whether Nav1.8+ nociceptor neurons or their specific subsets (CGRP+, MRGPRD+) are necessary for maintenance of gut epithelial cell function during homeostasis, and barrier protection against the enteric pathogens Salmonella Typhimurium or Citrobacter rodentium; 2) Determine whether chemogenetic (DREADD) or dietary ligand activation of nociceptor neurons is sufficient to induce changes in gut epithelial cells and barrier function; 3) Define the role of the nociceptor neuropeptide CGRP-RAMP1 axis in regulating barrier epithelial (goblet cells, M cells) and immune cells in modulating barrier host defenses. We aim to use innovative and interdisciplinary approaches from neurobiology, gastroenterology, and immunology to interrogate the role of nociceptor neurons in gut barrier function and enteric host defense. The team includes experts in nociceptor neurons and neuroimmunology (Chiu lab), and gut microbial and immune responses (Huh lab). A role for the nervous system in regulating gastrointestinal barrier defenses could lead to novel approaches to treat autoimmune and inflammatory diseases. A greater understanding of how neurons signal to epithelial cells and immune cells the gastrointestinal tract could lead to novel insights in tissue barrier homeostasis. Our findings could also have relevance to disease conditions where gut barrier dysfunction occur such as autoimmune or inflammatory diseases. Targeting neurons or CGRP signaling could therefore lead to novel approaches to enhance barrier integrity to treat gastrointestinal diseases.

项目总结 伤害性感受器神经元是密集支配胃肠道的外周感觉神经元，检测到 有害/有害的刺激，以调节包括疼痛在内的保护性神经反射。然而，伤害性感受器的作用 神经元或其在调节肠道生理、屏障保护和宿主防御中的分子介体不是 很好理解。这里我们假设，特定的肠道伤害性感受器向上皮细胞发出信号，以 在动态平衡和细菌入侵期间调节肠道屏障防御。我们的初步数据显示， 伤害性神经元和伤害性神经肽降钙素基因相关肽(CGRP)对肠道的信号传导 杯状细胞和微折叠(M)细胞，这是两种介导屏障保护和宿主的肠道上皮细胞 防御。最近对背根节神经元的分子表型研究表明，多种类型的伤害性感受器支配 我的直觉。在这个项目中，我们将利用有针对性的遗传和分子方法来：1)确定 NAV1.8+伤害性感受器神经元或其特定亚群(CGRP+、MRGPRD+)是维持中枢神经系统功能所必需的 肠道上皮细胞在动态平衡中的功能，以及对肠道病原体沙门氏菌的屏障保护 鼠伤寒沙门氏菌或齿柠檬酸杆菌；2)确定化学生成(DREADD)或饮食配体 伤害性感受器神经元的激活足以引起肠道上皮细胞和屏障功能的改变；3) 明确伤害性感受器神经肽CGRP-RAMP1轴在调节屏障上皮细胞(杯状细胞， M细胞)和免疫细胞参与调节屏障宿主防御。我们的目标是利用创新和跨学科 从神经生物学、胃肠病学和免疫学角度探讨伤害性感受器神经元的作用 在肠道屏障功能和肠道宿主防御方面。该团队包括伤害性感受器神经元和 神经免疫学(CHU实验室)和肠道微生物和免疫反应(HUH实验室)。一个给神经质的人的角色 调节胃肠道屏障防御的系统可能导致治疗自身免疫性和 炎症性疾病。对神经元如何向上皮细胞和免疫细胞发出信号有更深入的了解 胃肠道可能导致对组织屏障动态平衡的新见解。我们的发现也可能有 与发生肠道屏障功能障碍的疾病相关，如自身免疫性或炎症性 疾病。因此，靶向神经元或CGRP信号可能导致新的方法来增强屏障 诚信治疗胃肠道疾病。