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.

项目摘要伤害感受器神经元是周围感官神经元，可密度支配胃肠道，检测有害/有害刺激介导保护性神经反射，包括疼痛。但是，伤害感受器的角色神经元或其分子介质在调节肠道生理，障碍保护和宿主防御方面不是理解。在这里，我们假设特定的肠道伤害伤害感受器向上皮细胞发出信号调节稳态和细菌入侵期间的肠道屏障防御。我们的初步数据表明伤害感受器神经元和Nocptor神经肽降钙素基因相关肽（CGRP）信号至肠道杯状细胞和微膜细胞（M）细胞，两种类型的肠道上皮细胞，介导屏障保护和宿主防御。 DRG神经元的最近分子表型表明，多种类型的伤害感受器神经支配肠道。在这个项目中，我们将利用靶向的遗传和分子方法：1）确定是否确定是否是否 NAV1.8+Nocteptor神经元或其特定子集（CGRP+，MRGPRD+）对于维护是必要的稳态期间的肠道上皮细胞功能，以及针对肠道病原体的障碍保护伤寒或柠檬酸啮齿动物； 2）确定化学遗传（Dreadd）还是饮食配体伤害感受器神经元的激活足以诱导肠道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（Goblet细胞， M细胞）和免疫细胞调节屏障宿主防御能力。我们的目标是使用创新和跨学科来自神经生物学，胃肠病学和免疫学的方法来询问伤害感受器神经元的作用在肠道功能和肠宿主防御中。该团队包括Nocteptor神经元的专家和神经免疫学（CHIU实验室）和肠道微生物和免疫反应（HUH Lab）。紧张的角色调节胃肠道防御措施的系统可能会导致治疗自身免疫和的新方法炎症性疾病。对神经元如何向上皮细胞和免疫细胞发出信号的更多了解胃肠道可能导致组织屏障稳态的新见解。我们的发现也可能有与肠道屏障功能障碍（例如自身免疫或炎症）的疾病状况有关疾病。因此，靶向神经元或CGRP信号传导可能会导致新的方法来增强屏障治疗胃肠道疾病的完整性。