Reversal of Inflammatory Processes in CGD

CGD 中炎症过程的逆转

• 批准号: 8669607
• 负责人: DONNA L BRATTON
• 金额: $ 39.63万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669607
• 关键词: 2,4-thiazolidinedione; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Autoimmunity; Biochemical Genetics; Cartoons; Cells; Chronic; Chronic Granulomatous Disease; Colitis; Cytolysis; Data; Defect; Development; Disease; Environment; Excision; Functional disorder; Funding; Future; Granuloma; Granulomatous; Health; Hereditary Disease; Host Defense; Human; Immunologic Deficiency Syndromes; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Investigation; Lead; Leukocytes; Mediating; Modeling; Morbidity - disease rate; Mus; Mutation; NADPH Oxidase; Oxidants; Oxidases; Patients; Peroxisome Proliferator-Activated Receptors; Phagocytes; Pioglitazone; Process; Production; Public Health; Reactive Oxygen Species; Recruitment Activity; Resolution; Role; Signal Transduction; Source; Sterility; Thiazolidinediones; Wound Healing; fighting; in vitro Model; in vivo; insight; loss of function; macrophage; monocyte; neutrophil; novel therapeutic intervention; preclinical study; programs; restoration; therapeutic target

DESCRIPTION (provided by applicant): Chronic Granulomatous Disease (CGD) is a genetic disease resulting from mutation of the phagocyte NADPH oxidase. While loss of the functioning oxidase results in immunodeficiency, significant disease morbidity is associated with exaggerated, and often sterile, inflammation (e.g. obstructing granuloma, colitis and autoimmunity). Signals downstream of the NADPH oxidase provide necessary control of inflammation, but are poorly understood. Data support that signaling by apoptosing CGD neutrophils and their recognition and engulfment (efferocytosis) by CGD macrophages are defective; these processes ordinarily result in production of anti-inflammatory signals (e.g. TGFβ), and are required to resolve inflammation. Specifically, it is hypothesized that absence of reactive oxygen species from the NADPH oxidase results in: i) deficient display of signals on activated and dying CGD neutrophils needed to facilitate macrophage recognition and clearance, and ii) deficient macrophage PPARγ, a master controller of inflammation and macrophage programming for efferocytosis. Inflammatory programming persists in CGD with macrophages unable to clear dying neutrophils, which in turn, accumulate, deteriorate, and fuel exaggerated inflammation and autoimmunity. The specific aims of this investigation are to i) define the normal role of oxidants and PPARγ in macrophage programming and their relationship to underlying deficient efferocytosis and over-production of inflammatory mediators in CGD, ii) define the actions of PPARγ agonists in the restoration of CGD macrophage functioning and iii) define the role of oxidants produced by alternative mechanism(s) during PPARγ agonism in reversing the dysfunction of CGD neutrophils and macrophages. This investigation will be carried out in murine and human CGD neutrophils and monocyte/macrophages using sophisticated biochemical, genetic and pharmacological approaches. A well-defined model of granulomatous inflammation in murine CGD will be employed, and together with exploratory endpoints in human CGD phagocytes, will i) elucidate the interconnection between defective ROS production and miscued phagocyte function, and ii) determine whether, and how, restored PPARγ signaling reverses impaired efferocytosis and inflammatory responses. A new hypothesis to explain the persistent inflammatory response in CGD along with its mitigation through PPARγ will support a novel therapeutic approach. This investigation is intended to be a pre-clinical trial of an existing therapy, PPARγ agonists, available for treatment of CGD patients. A thorough understanding of macrophage programming and PPARγ signaling in the recognition and clearance of apoptotic cells in CGD and under normal circumstances is needed. Such findings should also give critical insight into other inflammatory disease states in which macrophage programming and recognition of apoptotic cells appears to be defective.

描述（由申请人提供）：慢性肉芽肿病（CGD）是一种由吞噬细胞NADPH氧化酶突变引起的遗传性疾病。虽然功能氧化酶的丧失导致免疫缺陷，但显著的疾病发病率与过度的且通常无菌的炎症（例如阻塞性肉芽肿、结肠炎和自身免疫）相关。NADPH氧化酶下游的信号提供了必要的炎症控制，但知之甚少。数据支持通过吞噬CGD嗜中性粒细胞的信号传导以及CGD巨噬细胞对其的识别和吞噬（吞噬作用）是有缺陷的;这些过程通常导致抗炎信号（例如TGF β）的产生，并且是解决炎症所需的。具体来说就是 假设NADPH氧化酶中活性氧的缺乏导致：i）活化和死亡的CGD嗜中性粒细胞上促进巨噬细胞识别所需的信号显示不足， 清除，以及ii）巨噬细胞PPAR γ缺陷，炎症和巨噬细胞的主要控制者 编程治疗红细胞增多症炎症编程在CGD中持续存在，巨噬细胞无法清除 死亡的中性粒细胞，其反过来积累、恶化并加剧炎症和自身免疫。 本研究的具体目的是：i）确定氧化剂和过氧化物酶体增殖物激活受体γ在巨噬细胞中的正常作用， 编程及其与潜在的缺乏性红细胞增多症和过度产生炎性细胞因子的关系 CGD中的介质，ii）定义了PPAR γ激动剂在CGD巨噬细胞功能恢复中的作用 和iii）确定在PPAR γ激动过程中由替代机制产生的氧化剂在逆转 CGD中性粒细胞和巨噬细胞的功能障碍。本研究将在小鼠和 人CGD嗜中性粒细胞和单核细胞/巨噬细胞，使用复杂的生物化学、遗传和 药理学方法。一个明确定义的小鼠CGD肉芽肿性炎症模型将是 使用的，并与人CGD吞噬细胞中的探索性终点一起，将i）阐明 有缺陷的ROS产生和错误的吞噬细胞功能之间的相互联系，和ii）确定 恢复的PPAR γ信号是否以及如何逆转受损的红细胞增多症和炎症反应。 一个新的假说来解释持续性炎症反应在CGD沿着其缓解，通过 PPAR γ将支持一种新的治疗方法。本研究旨在作为一项临床前试验， 现有的治疗，PPAR γ激动剂，可用于治疗CGD患者。的透彻理解 巨噬细胞编程和过氧化物酶体增殖物激活受体γ信号在识别和清除凋亡细胞中的作用 在正常情况下，这是必要的。这些发现也应该对其他炎症性疾病提供重要的见解。 疾病状态，其中巨噬细胞编程和凋亡细胞的识别似乎有缺陷。