Macrophage nuclear receptors, metabolism and immune effectors during health and M. tuberculosis infection

健康和结核分枝杆菌感染期间的巨噬细胞核受体、代谢和免疫效应器

基本信息

批准号：
10457308
负责人：
Larry S. Schlesinger
金额：
$ 70.68万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-07 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457308
关键词：
Agonist Air Allergens Alveolar Alveolar Macrophages Alveolus BCL2 gene Biochemical Genetics Biochemical Pathway Biological Biology Cause of Death Cell physiology Clinical Collectins Data Development Drug Targeting Eicosanoid Production Eicosanoids Environment Event Exposure to Failure Family Family member Gases Gene Expression Genes Genetic Techniques Genetic Transcription Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Health Homeostasis Human Immune Immune Response Genes Immune response Immune system Immunity Infection Inflammation Inflammatory Inhalation Interleukin-10 Laboratories Ligands Link Lipids Lung Lung immune response Lung infections MCL1 gene Maintenance Mediating Metabolic Metabolism Microbe Modeling Molecular Mus Mycobacterium tuberculosis NR4A2 gene Nuclear Receptors PPAR alpha PPAR gamma PTGS2 gene Pathogenesis Pathway interactions Pharmaceutical Preparations Proteins Pulmonary Surfactant-Associated Protein A Pulmonary alveolar structure Regulation Research Role Route S100A8 gene Sales Shapes Signal Pathway Signal Transduction Tissues Transforming Growth Factor beta Tuberculosis base cellular development cytokine eicosanoid metabolism global health human model immunoregulation in vitro Model in vivo inhibitor knock-down lipid mediator lipid metabolism mRNA Expression macrophage monocyte mouse model nano-string pathogen pollutant pre-clinical programs receptor expression response surfactant therapeutic target transcription factor treatment strategy tuberculosis treatment

项目摘要

Project Summary/Abstract Human lungs, while mediating air exchange in the alveoli, are constantly exposed to pollutants, allergens, and microbes. Resident alveolar macrophages (AMs) must clear insults without damaging the alveoli. Thus, AMs possess a unique, highly regulated immune response that results in inefficient clearance of some airborne microbes, especially host-adapted pathogens like Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), a top 10 cause of death worldwide. AM development, maintenance and biology are poorly understood, especially for human macrophages and in regards to the effect of the local environment, e.g. surfactant, which lines the alveoli, and locally produced cytokines such as TGFβ. Failure to completely understand the molecular events underlying AM development and biology creates a critical barrier to developing new treatment strategies that target the lung. The long-term objective of this ongoing research program is to identify signaling pathways associated with transcriptional regulators and inflammatory metabolites that dictate AM biology and how these are co-opted by the host-adapted intracellular pathogen M.tb, to enhance its growth. New data in the laboratory indicate that M.tb, surfactant proteins and TGFβ regulate expression of the nuclear receptors (NRs) peroxisome proliferator-activated receptor gamma (PPARγ), Rev-erbα, Nur77, and Nurr1. NRs are a large family of structurally conserved, ligand activated transcription factors, which enable macrophages to sense their local environment and shape immune responses. In this regard, NRs sit at the interface of metabolism (particularly lipid and eicosanoid) and immunity, and are increasingly recognized as relevant to M.tb pathogenesis, yet are unexplored in the context of the lung and M.tb. It is critical to understand if/how NRs cooperate to regulate AM biology in ways that impact responses to M.tb. Expression and function of NRs are tightly regulated to provide a balanced immune response. The hypothesis for this proposal is that NRs modify eicosanoid metabolism and protective immune responses, thereby making AMs more susceptible to M.tb and that M.tb augments select endogenous pathways to further dampen the AM immune response to enhance its survival. The Specific Aims are to: 1) determine the effect of surfactant and local cytokines on human macrophage NR expression and activity and how this is modulated by M.tb, 2) characterize newly discovered PPARγ effectors and their regulation of lipid metabolism during M.tb infection, and 3) determine whether PPARγ, Rev-erbα, Nur77 and Nurr1, as well as PPARγ effectors, are viable host-directed therapeutic targets for TB. Human AMs and the tractable model of human blood monocyte-derived macrophages (MDMs), biochemical and genetic techniques, and mouse models will be used to study the role of NRs, and their effectors, in TB. Since NRs regulate metabolism and inflammation in a tissue, gene and signal-specific manner, these findings open the door to a completely new set of biological pathways likely to be critical to host responses in the lung, during health and M.tb infection.

项目概要/摘要人的肺部在调节肺泡中的空气交换的同时，也不断暴露于污染物、过敏原和常驻肺泡巨噬细胞 (AM) 必须清除损伤而不损伤肺泡。具有独特的、高度调节的免疫反应，导致某些空气传播的病毒清除效率低下微生物，特别是适应宿主的病原体，如结核分枝杆菌 (M.tb)，它是结核病的病原体结核病 (TB) 是全球十大死亡原因，AM 的发育、维持和生物学状况都很差。理解，特别是对于人类巨噬细胞以及当地环境的影响，例如肺泡表面活性剂和局部产生的细胞因子（如 TGFβ）完全失败。了解 AM 发育和生物学背后的分子事件为开发针对肺部的新治疗策略是这项正在进行的研究的长期目标。计划是识别与转录调节因子和炎症相关的信号通路决定 AM 生物学的代谢物以及这些代谢物如何被适应宿主的细胞内病原体吸收 M.tb，促进其生长。实验室的新数据表明，M.tb、表面活性蛋白和 TGFβ。调节核受体 (NR) 过氧化物酶体增殖物激活受体 γ 的表达 (PPARγ)、Rev-erbα、Nur77 和 Nurr1 是一个结构保守、配体激活的大家族。转录因子，使巨噬细胞能够感知其局部环境并形成免疫在这方面，NR 位于代谢（特别是脂质和类二十烷酸）和免疫，并且越来越多地被认为与 M.tb 发病机制相关，但尚未在背景下进行探索了解 NR 是否/如何合作调节 AM 生物学至关重要对 M.tb 的影响反应 NR 的表达和功能受到严格调节，以提供平衡的免疫该提议的假设是 NR 可以改变类二十烷酸代谢和保护性免疫系统。反应，从而使 AM 更容易受到 M.tb 的影响，并且 M.tb 增强了选择的内源性进一步抑制 AM 免疫反应以增强其生存的途径具体目标是：1) 确定表面活性剂和局部细胞因子对人巨噬细胞 NR 表达和活性的影响， M.tb 如何对其进行调节，2) 描述新发现的 PPARγ 效应物及其对脂质的调节 M.tb 感染期间的代谢，3) 确定 PPARγ、Rev-erbα、Nur77 和 Nurr1 以及 PPARγ 效应子是人类 AM 和易处理的结核病模型的可行的宿主导向治疗靶点。人血单核细胞衍生巨噬细胞 (MDM)、生化和遗传技术以及小鼠由于 NR 调节新陈代谢和结核病，模型将用于研究 NR 及其效应物的作用。以组织、基因和信号特异性方式发生炎症，这些发现为一种全新的方法打开了大门在健康和结核分枝杆菌感染期间，一组生物途径可能对肺部的宿主反应至关重要。