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Neural sensing of gut bacteria

肠道细菌的神经感知

基本信息

批准号：
10456027
负责人：
Winston W Liu
金额：
$ 4.88万
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/10456027
关键词：
3-Dimensional Acute Address Bacteria Bathing Biology Brain Brain Stem Calcium Cells Chemicals Clinical Clinical Research Colon Data Dependence Detection Disease 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 Neuraxis 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 cell dimension cellular transduction commensal bacteria conditional knockout doctoral student extracellular gut bacteria gut microbiome hormonal signals in vivo intestinal epithelium microbial microbial community microbiome millisecond neural circuit neurotransmitter release novel optogenetics pathogen receptor relating to nervous system 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.

摘要