Role of Macrophage Arginase in Anti-Bacterial Immunity

巨噬细胞精氨酸酶在抗细菌免疫中的作用

• 批准号: 6850983
• 负责人: PETER J. MURRAY
• 金额: $ 26.25万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850983
• 关键词: arginase; bacterial disease; bactericidal immunity; bioinformatics; biological models; chromatin immunoprecipitation; chronic disease /disorder; enzyme activity; enzyme induction /repression; fibrosis; genetically modified animals; granuloma; host organism interaction; immune response; immunoregulation; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; nitric oxide; nitric oxide synthase; nuclear factor kappa beta; septic shock; septicemia; tuberculosis

DESCRIPTION (PROVIDED BY APPLICANT): The tight control of macrophage function is central to inflammatory and immune responses. Arginase I (Arg I) is a newly recognized marker of activated macrophages. The profound induction of normally silent Arg I expression in response to infectious agents, in asthma and in other diseases involving chronic inflammation suggests that new insights into macrophage function in immunity can be uncovered by understanding the biology of Arg I, and the pathways that converge to regulate its expression. However, a major gap in understanding Arg I function in the context of immune responses is the translation of correlative expression data and in vitro findings to in vivo systems because Arg I also plays an irreplaceable role in liver function. To address this problem, mouse models were developed where Arg I is specifically deleted or over-expressed in macrophages. The preliminary data establish the fidelity of these models and set the stage for a detailed examination of Arg I function in immune responses to bacteria. Infection models will be studied because Arg I function is most directly implicated in two pathways that regulate immunity to bacteria: nitric oxide (NO) biosynthesis and the promotion of fibrosis. Four aims are proposed to study Arg I biology in macrophages. In Aim 1, the role of Arg I in regulating the biogenesis of NO will be studied using systems deficient in Arg I. In Aim 2, the role of Arg I in regulating inflammation, tissue repair and NO biosynthesis in septic shock models will be dissected. In Aim 3, the function of Arg I in regulating the immunological and pathological outcomes in tuberculosis, a chronic disease that is dependent on exquisite control of NO levels for effective immunity, will be investigated. In Aim 4, we will extend our current studies of Arg I regulation in macrophages to determine how pathogens themselves induce expression. The outcomes of the proposed studies will reveal new elements of Arg I function and provide rationale for approaching Arg I as a target in inflammatory diseases.

描述（由申请人提供）：巨噬细胞功能的严格控制是炎症和免疫反应的核心。精氨酸酶I （Arg I）是新发现的活化巨噬细胞的标志物。在感染因子、哮喘和其他慢性炎症疾病中，正常情况下沉默的Arg I表达的深刻诱导表明，通过了解Arg I的生物学特性，以及聚集调节其表达的途径，可以揭示巨噬细胞在免疫中的功能。然而，了解Arg I在免疫应答中的功能的一个主要空白是将相关表达数据和体外研究结果翻译到体内系统，因为Arg I在肝功能中也起着不可替代的作用。为了解决这个问题，在巨噬细胞中特异性删除或过度表达Arg I的小鼠模型被开发出来。初步数据建立了这些模型的保真度，并为详细检查Arg I在对细菌的免疫反应中的功能奠定了基础。将研究感染模型，因为Arg I的功能最直接涉及调节细菌免疫的两条途径：一氧化氮（NO）生物合成和促进纤维化。本文提出了巨噬细胞中Arg I生物学研究的四个目标。在Aim 1中，我们将利用缺乏Arg I的系统研究Arg I在调节NO生物生成中的作用。在Aim 2中，我们将分析Arg I在感染性休克模型中调节炎症、组织修复和NO生物合成中的作用。在Aim 3中，将研究Arg I在调节结核病（一种依赖于精确控制NO水平以获得有效免疫的慢性疾病）的免疫和病理结果中的功能。在Aim 4中，我们将扩展目前在巨噬细胞中Arg I调控的研究，以确定病原体本身如何诱导表达。拟议的研究结果将揭示Arg I功能的新元素，并为将Arg I作为炎症性疾病的靶点提供理论依据。