Reversal of Inflammatory Processes in CGD

描述(申请人提供)：慢性肉芽肿性疾病(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会导致免疫缺陷，但严重的疾病发病率与夸大的、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。数据支持，通过调节cgd中性粒细胞及其识别和吞噬(吞噬)cgd巨噬细胞的信号是有缺陷的；这些过程通常导致产生抗炎信号(例如转化生长因子β)，并且是消炎所必需的。具体地说，它是 假设NADPH氧化酶没有活性氧物种导致：i)激活和死亡的CGD中性粒细胞上信号显示不足，这是促进巨噬细胞识别和 清除，以及ii)缺乏的巨噬细胞PPARγ，炎症和巨噬细胞的主控制器 泡泡吞噬的程序设计。炎症程序在CGD中持续存在，巨噬细胞无法清除 死亡的中性粒细胞，反过来积累、恶化，并助长炎症和自身免疫。 这项研究的具体目的是：1)确定氧化剂和PPARγ在巨噬细胞中的正常作用 程序化及其与潜在的气泡吞噬和炎性过度产生的关系 γ激动剂在恢复巨噬细胞功能中的作用 以及iii)确定交替机制(S)产生的氧化剂在PPARγ激动剂逆转中的作用 CGD中性粒细胞和巨噬细胞功能障碍。这项调查将在小鼠和 人CGD中性粒细胞和单核/巨噬细胞使用复杂的生化，遗传学和 药理学方法。一个明确的小鼠CGD肉芽肿性炎症模型将是 并与人CGD吞噬细胞的探索终点一起，I)将阐明 有缺陷的ROS产生和错误的吞噬细胞功能之间的相互联系，以及ii)确定 是否以及如何恢复PPARγ信号逆转受损的泡沫化和炎症反应。 解释CGD持续性炎症反应及其缓解的新假说 PPARγ将支持一种新的治疗方法。这项调查旨在成为一项临床前试验 现有的治疗方法是PPARγ激动剂，可用于治疗慢性阻塞性肺疾病患者。透彻地了解 巨噬细胞编程和PPARγ信号在识别和清除慢性萎缩性脑病和慢性萎缩性胃炎凋亡细胞中的作用 在正常情况下是需要的。这样的发现也应该给予对其他炎症性疾病的批判性洞察 巨噬细胞编程和对凋亡细胞的识别出现缺陷的疾病状态。

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.