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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要伤害感受器神经元是密集支配胃肠道的外周感觉神经元，检测介导保护性神经反射（包括疼痛）的有害/有害刺激。然而，伤害感受器的作用神经元或其分子介质在调节肠道生理、屏障保护和宿主防御方面的作用并不重要。很好理解。在这里，我们假设特定的肠道神经伤害感受器向上皮细胞发出信号，在稳态和细菌入侵期间调节肠道屏障防御。我们的初步数据表明伤害感受器神经元和伤害感受器神经肽降钙素基因相关肽 (CGRP) 向肠道发出信号杯状细胞和微褶皱 (M) 细胞是介导屏障保护和宿主的两种肠道上皮细胞防御。最近 DRG 神经元的分子表型表明，多种类型的伤害感受器支配肠道。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）确定是否 Nav1.8+ 伤害感受器神经元或其特定亚群（CGRP+、MRGPRD+）对于维持肠道上皮细胞在稳态过程中的功能，以及针对肠道病原体沙门氏菌的屏障保护鼠伤寒杆菌或啮齿类柠檬酸杆菌； 2) 确定是化学遗传学（DREADD）还是饮食配体伤害感受器神经元的激活足以诱导肠上皮细胞和屏障功能的变化； 3）定义伤害感受器神经肽 CGRP-RAMP1 轴在调节屏障上皮（杯状细胞、 M细胞）和免疫细胞调节宿主屏障防御。我们的目标是利用创新和跨学科从神经生物学、胃肠病学和免疫学的角度探讨伤害感受器神经元的作用肠道屏障功能和肠道宿主防御。该团队包括伤害感受神经元和神经免疫学（Chiu 实验室）以及肠道微生物和免疫反应（Huh 实验室）。神经紧张的角色调节胃肠道屏障防御的系统可能会带来治疗自身免疫性疾病的新方法炎症性疾病。更好地了解神经元如何向上皮细胞和免疫细胞发出信号胃肠道可能会给组织屏障稳态带来新的见解。我们的发现也可能有与发生肠道屏障功能障碍的疾病（例如自身免疫性或炎症）相关疾病。因此，针对神经元或 CGRP 信号传导可能会带来增强屏障的新方法诚信治疗胃肠疾病。