Neural sensing of gut bacteria

肠道细菌的神经感知

基本信息

批准号：
10671590
负责人：
Winston W Liu
金额：
$ 4.98万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671590
关键词：
3-Dimensional Acute Address Bacteria Bathing Biology Brain Brain Stem Calcium Cell Communication Cells Central Nervous System Chemicals Classification Clinical Colon Communication Data Dependence Detection Disease Dissociation Enteroendocrine Cell Epithelial Cells Esthesia Flagellin Gastroenterology Gastrointestinal Diseases Glutamate Transporter Glutamates Hormones Human Image In Vitro Ingestion International Intestines Irritable Bowel Syndrome Knock-out Knowledge Laboratories Ligands Link Measures Mediating Mentors Metabolic syndrome Microbe Molecular Mus Names Nerve Neurobiology Neurosciences Neurotransmitters Nutrient Obesity Organoids Patients Pattern Pattern recognition receptor Pelvis Peptide YY Pharmacology Physicians Population Postdoctoral Fellow Reporting Research Project Grants Research Training Role Sacral nerve Science Scientist Sensory Signal Transduction Societies Specificity Synapses TLR5 gene Techniques Testing Therapeutic Training Training Support United States National Institutes of Health Visceral Weight Gain burden of illness career preparation cellular transduction clinical training commensal bacteria conditional knockout doctoral student extracellular gut bacteria gut microbiome hormonal signals in vivo intestinal epithelium microbial microbial community microbiome millisecond neural neural circuit neurotransmitter release novel optogenetics pathogen pharmacologic receptor response sensory mechanism skills symposium therapeutic target tool

项目摘要

ABSTRACT The gut continuously senses resident bacteria, but how the brain recognizes these microbes remains unclear. Microbe-associated molecular patterns such as flagellin are detected by the intestinal epithelium by pattern recognition receptors such as Toll-like receptor 5. Recent reports have shown that knocking out this receptor in the gut leads to metabolic syndrome. Pattern recognition receptors are also known to be preferentially expressed on enteroendocrine cells, or electrically excitable epithelial cells traditionally thought to signal hormonally. The sponsor’s laboratory has recently discovered that some of these cells, now known as neuropod cells, are synaptically connected with vagal and pelvic nerves. My preliminary data show that the neuropod cells preferentially express Toll-like receptor 5, and that conditionally knocking out the receptor in neuropod cells leads to weight gain in mice. These data suggest that neuropod cells are critical intermediaries in bacterial signaling from gut to brain. Therefore, the central hypothesis of the research project is that neuropod cells transduce flagellin in the lumen of the colon onto the sacral nerve through a synapse. To test this, two aims are proposed: (1) to determine whether neuropod cells release glutamate in response to flagellin in vitro, and (2) to test neuropod cell transduction of flagellin onto the sacral nerve in vivo. To address these aims, state-of-the-art techniques from intestinal epithelial biology and neurobiology will be combined by the trainee. In Aim 1, acutely dissociated neuropod cells and 3-dimensional organoid cultures will be imaged for calcium activity and glutamate release in response to flagellin. In Aim 2, optogenetic and pharmacological silencing of neuropod cells in sacral nerve recordings will be used to test whether the circuit transduces bacterial signals. These studies are expected to uncover a novel mechanism for microbes to communicate with the central nervous system that can be used to develop therapeutics for patients with gastrointestinal disease. This proposal will ultimately support the training of a dual-degree MD/PhD student, in preparation for his career as an independent physician-scientist at the intersection of a clinical gastroenterology practice and a neuroscience laboratory. The training plan will also include attending conferences and participating in organizing an international society of gut-brain scientists started by his sponsor named Gastronauts. With the support of this F30, the trainee will develop the requisite skill set to transition into post-doctoral clinical and research training on the path to becoming an independent physician scientist.

抽象的肠道继续说出居民细菌，但大脑如何识别这些微生物不清楚。肠检测图案识别受体（例如Toll-like受体5）上皮。最近的报道已显示在肠道中淘汰该受体会导致代谢综合征。模式识别受体也已知最好在肠内分泌细胞上表达，或者电上令人兴奋传统上，上皮细胞在荷尔蒙上发出信号。赞助商的实验室最近有发现这些细胞中的一些（现在称为神经脚类细胞）与迷走神经和骨盆神经。我的初步数据表明，神经足类细胞优先表达 Toll样受体5，并且有条件地敲除神经足类细胞中的受体导致重量在小鼠中获得。这些数据表明，神经足类细胞是细菌信号中的关键中间体从肠道到大脑。因此，研究项目的核心假设是神经脚架细胞通过突触将结肠腔中的鞭毛蛋白传播到骨神经上。为了测试这一点，提出了两个目的：（1）确定神经足类细胞是否响应于体外鞭毛蛋白，（2）测试鞭毛蛋白在体内的神经蛋白转移到s骨神经。到解决这些目的，肠上皮生物学和神经生物学的最先进技术将由实习生组合。在AIM 1中，急性解离神经脚类细胞和3维器官培养物将成像以响应鞭毛蛋白而成像钙活性和谷氨酸释放。在AIM 2中，将使用神经足类细胞的光遗传学和药物沉默在萨斯神经记录中测试电路是否传递细菌信号。这些研究有望发现微生物与中枢神经系统通信的新型机制可用于为胃肠道疾病患者开发理论。该建议最终将支持培训双度MD/PhD学生，为他的独立职业做准备临床胃肠病学实践与神经科学的交集的身体科学家实验室。培训计划还将包括参加会议并参加组织一个国际肠道科学家学会由他的赞助商名为Gastronauts创立。与对此F30的支持，受训者将发展必要的技能，以过渡为博士后临床以及成为成为独立物理科学家的道路的研究培训。