Reversal of Inflammatory Processes in CGD

CGD 中炎症过程的逆转

• 批准号: 8803304
• 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/8803304
• 关键词: 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. TGFß), 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 PPAR?\γ 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（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。虽然功能性氧化酶的丧失会导致免疫缺陷，但显着的疾病发病率与过度且通常是无菌的炎症（例如阻塞性肉芽肿、结肠炎和自身免疫）有关。 NADPH 氧化酶下游的信号提供了必要的炎症控制，但人们对此知之甚少。数据表明，CGD 中性粒细胞凋亡的信号传导以及 CGD 巨噬细胞对它们的识别和吞噬（胞吞作用）是有缺陷的； 这些过程通常会产生抗炎信号（例如 TGFβ），并且是解决炎症所必需的。具体来说，假设 NADPH 氧化酶中活性氧的缺失会导致：i) 促进巨噬细胞识别和清除所需的激活和死亡 CGD 中性粒细胞上的信号显示不足，以及 ii) 巨噬细胞 PPARγ 缺陷，PPARγ 是炎症和巨噬细胞胞吞作用的主要控制者。 CGD 中的炎症程序持续存在，巨噬细胞无法清除垂死的中性粒细胞，进而积累、恶化并加剧炎症和自身免疫。本研究的具体目的是 i) 定义氧化剂和 PPARγ\γ 在巨噬细胞编程中的正常作用及其与 CGD 中潜在的胞吞作用缺陷和炎症介质过度产生的关系，ii) 定义 PPARγ 激动剂在 CGD 巨噬细胞功能恢复中的作用，以及 iii) 定义在 CGD 过程中替代机制产生的氧化剂的作用 PPARγ 激动剂可逆转 CGD 中性粒细胞和巨噬细胞的功能障碍。这项研究将使用复杂的生化、遗传和药理学方法在小鼠和人类 CGD 中性粒细胞和单核细胞/巨噬细胞中进行。将采用小鼠 CGD 中明确的肉芽肿性炎症模型，并与人类 CGD 吞噬细胞的探索性终点一起，i) 阐明有缺陷的 ROS 产生与错误的吞噬细胞功能之间的相互关系，ii) 确定恢复的 PPARγ 信号是否以及如何逆转受损的胞吞作用和炎症反应。解释 CGD 中持续炎症反应及其通过 PPARγ 缓解的新假设将支持一种新的治疗方法。这项研究旨在对现有疗法 PPARγ 激动剂进行临床前试验，该疗法可用于治疗 CGD 患者。需要彻底了解 CGD 和正常情况下巨噬细胞编程和 PPARγ 信号在识别和清除凋亡细胞中的作用。这些发现还应该为其他炎症性疾病状态提供重要的见解，在这些状态中，巨噬细胞编程和凋亡细胞的识别似乎有缺陷。