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.

项目总结 在美国，肠道感染和炎症性肠病(IBD)会导致很大的发病率，并消耗 很大一部分卫生保健资源。对肠道健康和肠道内宿主微生物动态的认识有限 疾病是旨在提高免疫力和减少炎症的治疗的障碍。有一个很大的不- 满足了对肠道上皮在与肠道基质的沟通中的作用的基本了解的需要 特里亚。这个项目的长期目标是发现在体内参与的调控通路。 肠道上皮中宿主防御基因的诱导。本提案的总体目标是 确定调控PLC-PKD-TFEB(线虫中PLC-1/DKF-1/HLH-30)通路的上游机制- 我们在前一个资助期确定的方式，以及它驱动基因的下游机制 归纳法。中心假说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，这是重要的寄主防御在肠道。这个 这项拟议的研究的基本原理是，完全理解神经系统如何与 整个PLC-1/DKF-1/HLH-30通路对于基本理解寄主防御是必不可少的，而且 更好地掌握它的工作机制是必要的，以利用它作为治疗炎症或 感染。为了检验中心假设，我们提出了以下具体目标：1)确定 神经系统中HLH-30/TFEB的激活，通过定义检测感染的神经元，靶向远端 2)确定DKF-1/PKD和HLH-1之间的联系。 30/TFEB，通过反向遗传学、HLH-30/TFEB磷酸化分析和确定蛋白质-蛋白质相互作用；以及 3)确定下游转录因子在介导HLH-30/TFEB功能中的作用，通过肠道- 特定的功能丧失和转录特征。拟议研究的预期贡献是 明确胆碱能神经系统在控制PLC-PKD-TFEB通路及其下游的作用 体内感染过程中的流转录因子网络。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，并将使未来的治疗方法的发展操纵新兴的毒鼠强- 受控转录网络。提出的研究具有极大的创新性，因为PLC-PKD- TFEB途径还没有在任何背景下被研究过，因此所提出的研究具有极大的创新性。 这里提出的研究通过转移重点，代表了对现状的新的和实质性的偏离 到一个新发现的PLC-PKD-TFEB介导的新的神经系统-肠道信号轴 路径。拟议的工作克服了全面了解东道主防御的许多障碍， 并具有加速开发针对新兴麝香的创新疗法的巨大潜力- 用于治疗感染性或炎症性疾病的内分泌调控转录网络。