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.

抽象的肠道感觉不断存在细菌，但大脑如何识别这些微生物仍然存在肠道检测到的微生物相关分子模式（例如鞭毛蛋白）尚不清楚。上皮细胞通过模式识别受体（例如 Toll 样受体 5）进行识别。最近的报告表明敲除肠道中的这种受体会导致代谢综合征。还已知优先在肠内分泌细胞上表达，或可电兴奋传统上认为上皮细胞可以发出激素信号。申办者的实验室最近发现了这一点。发现其中一些细胞，现在被称为神经足细胞，与突触相连我的初步数据显示神经足细胞优先表达。 Toll 样受体 5，有条件地敲除神经足细胞中的受体会导致体重增加这些数据表明神经足细胞是细菌信号传导的关键中介。因此，该研究项目的中心假设是神经足细胞。通过突触将结肠腔中的鞭毛蛋白转导到骶神经上。提出了两个目标：（1）确定神经足细胞是否响应于释放谷氨酸（2）在体内测试鞭毛蛋白到骶神经的神经足细胞转导。为了实现这些目标，肠上皮生物学和神经生物学的最先进技术将由受训者组合在目标 1 中，急性分离的神经足细胞和 3 维类器官。在目标 2 中，将对培养物响应鞭毛蛋白的钙活性和谷氨酸释放进行成像。将使用骶神经记录中神经足细胞的光遗传学和药理学沉默测试该电路是否转导细菌信号。这些研究有望揭示一个问题。微生物与中枢神经系统通讯的新机制可用于开发针对胃肠道疾病患者的治疗方法最终将得到支持。对双学位医学博士/博士生的培训，为他的独立职业生涯做好准备临床胃肠病学实践和神经科学交叉领域的医师科学家实验室培训计划还将包括参加会议和参与组织。一个由肠脑科学家组成的国际学会由他的赞助人“Gastronauts”发起。在该 F30 的支持下，学员将培养过渡到博士后临床所需的技能以及成为独立医师科学家之路上的研究培训。