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Nervous system control of intestinal host defense mediated by TFEB

TFEB介导的神经系统对肠道宿主防御的控制

基本信息

批准号：
10537135
负责人：
Javier Elbio Irazoqui
金额：
$ 46.62万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10537135
关键词：
Address Afferent Neurons Animals Bacteria Bacterial Infections Biological Assay Brain Brain imaging Caenorhabditis elegans Cessation of life Chemicals Communication Cytokine Receptors Data Defense Mechanisms Development Diagnostic Disease Ear Event Family Funding Gene Expression Gene Expression Regulation Gene Proteins Genes Genetic Genetic Transcription Genomic approach Goals Grant Health Homeostasis Host Defense Human Ice In Vitro Infection Inflammation Inflammatory Ink Innovative Therapy Intestines Kinetics Knowledge Link Maps Mediating Mediator of activation protein Methods Microbe Microscopy Mission Mus Names Natural Immunity Nematoda Nerve Nerve Degeneration Nervous System control Nervous system structure Neurons Nuclear Orphan Receptor Nuclear Receptors Organism Orphan Outcome Pathogen detection Pathway interactions Peripheral Public Health Regulation Reporter Research Resistance to infection Role Sensory Signal Transduction Staphylococcus aureus System Testing Therapeutic Time Tissues Translating United States National Institutes of Health Work cholinergic cholinergic neuron chromatin immunoprecipitation defense response enteric infection gain of function human disease improved in vivo innovation knock-down macrophage microbial microbiota microbiota-gut-brain axis neural circuit novel optogenetics pathogen pathogenic bacteria prevent receptor sensory mechanism targeted treatment time use transcription factor

项目摘要

A few years ago, we discovered that HLH-30/TFEB, which belongs to the MiT transcription factor family, is essential for C. elegans defense against bacterial infections in the intestine. We also discovered that TFEB is important for pro-inflammatory polarization of mouse macrophages, and thus its function in innate immunity is evolutionarily conserved. The long-term goal of this project is to understand the sequence of events linking pathogen detection, organismal signal transduction, and host defense induction via HLH-30/TFEB. In the previous funding period, we discovered that the nervous system is required for HLH-30 activation in peripheral tissues. We also uncovered two opposing mechanisms of gene regulation downstream of HLH-30, mediated by uncharacterized orphan nuclear receptors (NRs). Currently there is little information on the mechanisms by which the nervous system regulates MiT factor-mediated mechanisms of innate immunity and inflammation in any organism. Moreover, such MiT-mediated defense mechanisms are largely unknown. These are important knowledge gaps that impede fundamental understanding of homeostasis and host defense, and that conceal therapeutic opportunities to treat infections or inflammatory diseases. The overall objectives of this project are to elucidate the roles of sensory neurons in sensing bacterial pathogens and microbiota to activate HLH-30/TFEB, and of HLH-30-regulated NRs. The central hypothesis is that specific bacteria, through their action on sensory neural circuits, induce the cholinergic nervous system to activate HLH-30/TFEB in target tissues, thus eliciting a specific host defense response that is modulated by conserved orphan nuclear receptors. To test this hypothesis, we will define regulation of HLH-30/TFEB by the nervous system and define mechanisms of action for two NRs downstream of TFEB. The proposed research is technically innovative because of innovations in the application of single-neuron and “whole brain” imaging to live infected animals in real time, and in the use of knockdown strategies in primary mouse macrophages to translate the C. elegans findings on the transcriptional mediators of TFEB functions in innate immunity. Additionally, the proposed work is conceptually innovative for its implication of specific neurons as part of a novel mechanism of microbiota/infection sensing and inter-tissue communication with the intestine, and for identifying mechanistic links among intestinal infection and neuronal degeneration within a TFEB-mediated mechanism of the microbiota-gut-brain axis. This proposal is highly relevant to human health because it focuses on genes and pathways that are conserved, and directly linked to disease in humans. This proposal is highly significant in the context of fundamental knowledge of the brain-gut-microbiota axis because it directly addresses important knowledge gaps and successful completion of the work will greatly advance our knowledge about the interplay among microbes, nerves, and innate immunity. This will have an important positive impact, because such knowledge will reveal novel host-directed therapeutic opportunities for a broad range of infectious and inflammatory diseases.

几年前，我们发现属于MIT转录因子家族的HLH-30/TFEB对于线虫抵御肠道细菌感染是必不可少的。我们还发现，TFEB对小鼠巨噬细胞的促炎极化很重要，因此它在天然免疫中的功能是进化保守的。这个项目的长期目标是了解通过HLH-30/TFEB连接病原体检测、生物信号转导和宿主防御诱导的一系列事件。在之前的资助期，我们发现神经系统是外周组织中HLH-30激活所必需的。我们还发现了两种相反的基因调控机制，由未鉴定的孤儿核受体(NRs)介导的HLH-30下游。目前，关于神经系统调节MIT因子介导的任何生物体的先天免疫和炎症机制的机制的信息很少。此外，这种由麻省理工学院介导的防御机制在很大程度上是未知的。这些是重要的知识鸿沟，阻碍了对动态平衡和宿主防御的基本了解，并掩盖了治疗感染或炎症性疾病的机会。本项目的总体目标是阐明感觉神经元在感知细菌病原体和微生物群激活HLH-30/TFEB以及HLH-30调节的NRs中的作用。中心假设是，特定的细菌通过它们对感觉神经回路的作用，诱导胆碱能神经系统激活靶组织中的HLH-30/TFEB，从而引发受保守的孤儿核受体调节的特定宿主防御反应。为了验证这一假设，我们将定义神经系统对HLH-30/TFEB的调节，并定义TFEB下游两个NRs的作用机制。这项拟议的研究在技术上具有创新性，因为它在应用单神经元和“全脑”成像技术对活体感染动物进行实时成像，以及在原代小鼠巨噬细胞中使用击倒策略来翻译线虫在天然免疫中TFEB功能的转录介质方面的发现方面具有创新。此外，拟议的工作在概念上是创新的，因为它将特定的神经元作为微生物区系/感染感知和与肠道的组织间通信的新机制的一部分，并在TFEB介导的微生物区系-肠道-脑轴的机制中识别肠道感染和神经元变性之间的机制联系。这一建议与人类健康高度相关，因为它关注的是保守的、与人类疾病直接相关的基因和途径。这一建议在脑-肠道-微生物区轴的基础知识背景下具有非常重要的意义，因为它直接解决了重要的知识缺口，成功完成这项工作将极大地促进我们对微生物、神经和先天免疫之间相互作用的知识。这将产生重要的积极影响，因为这些知识将揭示针对广泛的传染病和炎症性疾病的宿主指导的新的治疗机会。