Nociceptor neuron regulation of gastrointestinal barrier protection and host defense

项目摘要 伤害感受器神经元是密集地支配胃肠道的外周感觉神经元，检测胃肠道的伤害。 有害/有害刺激介导保护性神经反射，包括疼痛。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学、屏障保护和宿主防御中的作用， 很好理解。在这里，我们假设特定的肠神经伤害感受器向上皮细胞发出信号， 在体内平衡和细菌入侵期间调节肠道屏障防御。初步数据显示， 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）信号传递到肠 杯状细胞和微褶（M）细胞，两种类型的肠上皮细胞介导屏障保护和宿主 的防御合作. DRG神经元的最新分子表型表明，多种类型的伤害感受器支配 内脏在本项目中，我们将利用靶向遗传和分子方法：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 肠上皮细胞在体内平衡过程中的功能，以及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）确定是否是化学发生（DREADD）或饮食配体 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-RAMP 1轴在调节屏障上皮（杯状细胞， M细胞）和免疫细胞在调节屏障宿主防御中的作用。我们的目标是利用创新和跨学科的 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 在肠道屏障功能和肠道宿主防御中的作用。该团队包括伤害感受器神经元方面的专家， 神经免疫学（Chiu实验室）和肠道微生物和免疫应答（Huh实验室）。紧张的角色 调节胃肠道屏障防御系统可能导致治疗自身免疫性疾病的新方法， 炎症性疾病。更深入地了解神经元如何向上皮细胞和免疫细胞发出信号， 胃肠道可能导致组织屏障稳态的新见解。我们的发现也可能 与发生肠屏障功能障碍的疾病状况的相关性， 疾病因此，靶向神经元或CGRP信号传导可能导致新的方法来增强屏障 治疗胃肠疾病。

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.