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：
9567180
负责人：
Javier Elbio Irazoqui
金额：
$ 33.5万
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 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9567180
关键词：
Acetylcholine Address Afferent Neurons Animal Model Autoimmune Process Biological Caenorhabditis elegans Communication Cues Data Defect Detection Development Diglycerides Disease Distal Duct (organ) structure Enteral Epithelial Funding Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Goals Health Healthcare Host Defense Host Defense Mechanism Human Immune response Immunity Infection Infection Control Inflammation Inflammatory Inflammatory Bowel Diseases Innovative Therapy Intestines Irritable Bowel Syndrome Knowledge LIF gene Light Link Malignant Neoplasms Mammals Manipulative Therapies Mediating Microbe Mission Molecular Morbidity - disease rate Muscarinic Acetylcholine Receptor Muscarinics Nematoda Nervous System control Nervous system structure Neuroepithelial Neurons Outcome Pathogen detection Pathway interactions Phenotype Phospholipase C Phosphotransferases Protein Kinase Public Health Regulation Regulator Genes Regulatory Pathway Research Resources Role Sepsis Signal Pathway Signal Transduction Testing Time Tissues Translations United States National Institutes of Health Work cholinergic gene induction grasp gut bacteria host microbiota human disease in vivo innovation insight intestinal epithelium loss of function novel pathogen protein kinase D protein protein interaction response reverse genetics targeted treatment therapeutic target therapy development transcription factor

项目摘要

PROJECT SUMMARY In the U.S., enteric infections and inflammatory bowel diseases (IBD) cause great morbidity and consume a large portion of health-care resources. Limited knowledge of the host-microbe dynamic in intestinal health and disease is a barrier for therapies aimed at boosting immunity and reducing inflammation. There is a large un- met need for fundamental understanding of the role of the intestinal epithelium in communication with gut bac- teria. The long-term goal of this project is to uncover regulatory pathways that are engaged in vivo for the in- duction of host defense genes in the intestinal epithelium. The overall objective of the present proposal is to identify upstream mechanisms that regulate the PLC-PKD-TFEB (PLC-1/DKF-1/HLH-30 in C. elegans) path- way that we identified in the previous funding period, and downstream mechanisms by which it drives gene induction. The central hypothesis is that the cholinergic nervous system controls the PLC-1/DKF-1/HLH-30 pathway, which induces a transcription factor cascade that is important for host defense in the intestine. The rationale for the proposed research is that complete understanding of how the nervous system interacts with the entire PLC-1/DKF-1/HLH-30 pathway is essential for fundamental understanding of host defense, and that a better grasp of its workings is necessary to harness its potential as a therapeutic target for inflammation or infection. To test the central hypothesis, we propose the following specific aims: 1) Determine the role of the nervous system in the activation of HLH-30/TFEB, by defining neurons that detect infection, the target distal tissues, and pathogen genes necessary for detection; 2) Define the link between DKF-1/PKD and HLH- 30/TFEB, by reverse genetics, HLH-30/TFEB phosphoanalysis, and defining protein-protein interactions; and 3) Determine the role of downstream transcription factors in mediating HLH-30/TFEB function, by intestine- specific loss of function and transcriptional profiling. The expected contribution of the proposed research is to define the role of the cholinergic nervous system in controlling the PLC-PKD-TFEB pathway and its down- stream transcription factor network during infection in vivo. This contribution is significant because it will repre- sent a leap forward for understanding the molecular basis of regulation of the epithelial barrier by the nervous system, and will enable the future development of therapies that manipulate the emerging muscarinic- controlled transcriptional network. The proposed research is extremely innovative because the PLC-PKD- TFEB pathway has not been studied in any context, and thus the proposed research is extremely innovative. The research proposed here represents a new and substantive departure from the status quo, by shifting focus to a new nervous system-intestinal signaling axis that is mediated by the newly uncovered PLC-PKD-TFEB pathway. The proposed work overcomes many barriers to the comprehensive understanding of host defense, and has great potential to accelerate the development of innovative therapies that target the emerging musca- rinic-controlled transcriptional network to treat infectious or inflammatory diseases.

项目概要在美国，肠道感染和炎症性肠病 (IBD) 造成很高的发病率并消耗大量医疗保健资源的很大一部分。对肠道健康中宿主微生物动态的了解有限疾病是旨在增强免疫力和减少炎症的治疗的障碍。有一个很大的联合国满足了对肠上皮在与肠道细菌沟通中的作用的基本了解的需要泰里亚。该项目的长期目标是揭示体内参与的调控途径肠道上皮细胞中宿主防御基因的诱导。本提案的总体目标是确定调节 PLC-PKD-TFEB（线虫中的 PLC-1/DKF-1/HLH-30）路径的上游机制我们在上一个资助期间确定的方式，以及它驱动基因的下游机制就职。中心假设是胆碱能神经系统控制 PLC-1/DKF-1/HLH-30 途径，它诱导转录因子级联，这对于肠道内的宿主防御很重要。这拟议研究的基本原理是完全了解神经系统如何与整个 PLC-1/DKF-1/HLH-30 通路对于基本了解宿主防御至关重要，并且有必要更好地掌握其工作原理，以利用其作为炎症或治疗靶点的潜力感染。为了检验中心假设，我们提出以下具体目标：1）确定 HLH-30/TFEB 激活中的神经系统，通过定义检测感染的神经元，目标远端检测所需的组织和病原体基因； 2) 定义DKF-1/PKD和HLH-之间的链接 30/TFEB，通过反向遗传学、HLH-30/TFEB 磷酸分析和定义蛋白质-蛋白质相互作用；和 3) 通过肠道确定下游转录因子在介导 HLH-30/TFEB 功能中的作用特定功能丧失和转录谱。拟议研究的预期贡献是定义胆碱能神经系统在控制 PLC-PKD-TFEB 通路及其下调中的作用体内感染期间的转录因子网络。这一贡献意义重大，因为它将代表为理解神经调节上皮屏障的分子基础带来了飞跃系统，并将促进未来开发操纵新兴毒蕈碱的疗法受控转录网络。所提出的研究极具创新性，因为 PLC-PKD- TFEB 通路尚未在任何背景下进行过研究，因此拟议的研究极具创新性。这里提出的研究代表了对现状的新的实质性偏离，通过转移焦点到一个新的神经系统-肠道信号轴，该轴由新发现的 PLC-PKD-TFEB 介导途径。拟议的工作克服了全面理解宿主防御的许多障碍，并具有加速开发针对新兴麝香病毒的创新疗法的巨大潜力 rinic 控制的转录网络用于治疗传染性或炎症性疾病。