Reversal of Inflammatory Processes in CGD

CGD 中炎症过程的逆转

基本信息

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
项目类别：
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

项目摘要

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，虽然氧化酶功能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有关。 NADPH 氧化酶下游的信号提供了必要的控制。炎症，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及其被 CGD 巨噬细胞的识别和吞噬（胞吞作用）是有缺陷的；这些过程通常会导致抗炎信号（例如 TGFβ）的产生，并且需要解决这一问题。具体来说就是炎症。准备好 NADPH 氧化酶中缺乏活性氧会导致：i) 促进巨噬细胞识别和死亡所需的激活和死亡 CGD 中性粒细胞上的信号显示不足清除，以及 ii) 巨噬细胞 PPARγ 缺陷，它是炎症和巨噬细胞的主要控制者 CGD 中巨噬细胞无法清除炎症程序。垂死的中性粒细胞反过来会积累、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 PPARγ 在巨噬细胞中的正常作用编程及其与潜在的胞吞作用缺陷和炎症过度产生的关系 CGD 中的介质，ii) 定义 PPARγ 激动剂在恢复 CGD 巨噬细胞功能中的作用 iii) 定义 PPARγ 激动过程中替代机制产生的氧化剂在逆转中的作用这项研究将在小鼠和巨噬细胞中进行。人类 CGD 中性粒细胞和单核细胞/巨噬细胞使用复杂的生化、遗传和小鼠 CGD 肉芽肿性炎症的明确模型将是。采用，并与人类 CGD 吞噬细胞的探索性终点一起，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关系，以及 ii) 确定恢复的 PPARγ 信号传导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缓解的新假说 PPARγ 将支持一种新的治疗方法。这项研究旨在成为一种临床前试验。现有疗法，PPARγ激动剂，可用于治疗CGD患者。巨噬细胞编程和 PPARγ 信号在 CGD 和凋亡细胞识别和清除中的作用在正常情况下，这些发现也应该为其他炎症提供重要的见解。巨噬细胞编程和凋亡细胞识别似乎有缺陷的疾病状态。