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; 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对于炎症和免疫反应至关重要。精氨酸酶I（arg I）是活化巨噬细胞的新认识的标记。在哮喘和其他涉及慢性炎症的疾病中，对正常静音ARG I表达的强烈诱导表明，可以通过理解ARG I的生物学以及融合其表达的途径来发现对巨噬细胞功能的新见解。但是，理解ARG I在免疫反应背景下的功能的主要差距是相关表达数据和体外发现向体内系统的翻译，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，开发了鼠标模型，其中ARG I在巨噬细胞中被特异性删除或过表达。初步数据确定了这些模型的保真度，并为对细菌的免疫反应中的ARG I功能进行了详细研究奠定了基础。将研究感染模型，因为ARG I功能最直接地与调节细菌免疫的两种途径有关：一氧化氮（NO）生物合成和促进纤维化。提出了四个目标来研究巨噬细胞中的ARG I生物学。在AIM 1中，将使用ARG I中缺乏系统研究ARG I在调节NO的生物发生中的作用。在AIM 3中，将研究ARG I在调节结核病的免疫学和病理结局中的功能，该慢性疾病将依赖于对无水平的有效免疫的精致控制。在AIM 4中，我们将扩展当前对巨噬细胞中ARG I调节的研究，以确定病原体本身如何诱导表达。拟议的研究的结果将揭示ARG I功能的新元素，并为接近ARG I作为炎症性疾病的目标提供了理由。