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

• 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
• 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

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.

项目摘要 在美国，肠道感染和炎症性肠病（IBD）引起了极大的发病率并消耗 大部分医疗资源。对肠道健康方面的宿主微叶动态知识有限 疾病是旨在增强免疫力和减少炎症的疗法的障碍。有一个大的 满足了对肠上皮在与肠道交流中的作用的基本了解的需求 特里亚。该项目的长期目标是揭示与体内参与体内的监管途径 在肠上皮中宿主防御基因的作用。本提案的总体目标是 确定调节PLC-PKD-TFEB（秀丽隐杆线虫中PLC-1/DKF-1/HLH-30）路径的上游机制 - 我们在上一个资金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，该途径诱导转录因子级联对于肠中的宿主防御很重要。这 拟议研究的理由是，完全了解神经系统如何与 整个PLC-1/DKF-1/HLH-30途径对于对宿主防御的基本了解至关重要，并且 更好地掌握其工作是必要的，以利用其作为炎症或 感染。为了检验中心假设，我们提出以下特定目的：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，靶向远端 组织和病原体基因检测； 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，并定义蛋白质 - 蛋白质相互作用；和 3）确定下游转录因子在介导HLH-30/TFEB功能中的作用， 功能和转录分析的特定丧失。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途径及其下的作用 在体内感染期间，流转录因子网络。这项贡献很重要，因为它将代表 向前迈出了一个飞跃，以理解神经上皮屏障的分子基础 系统，并将使未来的疗法开发，以操纵新兴的毒蕈碱 - 受控的转录网络。拟议的研究具有极其创新性，因为PLC-PKD- 在任何情况下，尚未对TFEB途径进行研究，因此拟议的研究非常创新。 这里提出的研究代表了与现状的新事物，通过转移重点 到由新发现的PLC-PKD-TFEB介导的新神经系统 - 肠信号传导轴 路径。拟议中的工作克服了对寄宿国防的全面理解的许多障碍， 并具有巨大的潜力，可以加速针对新兴穆斯卡的创新疗法的发展 RINIC控制的转录网络，以治疗传染病或炎症性疾病。