Role of NADPH Oxidase in Regulating Inflammation

描述(申请人提供)：慢性肉芽肿性疾病(CGD)是一种罕见的NADPH氧化酶复合体遗传性疾病，吞噬细胞在产生超氧阴离子和下游活性氧化中间产物(ROI)方面存在缺陷。CGD的特点是反复发生危及生命的细菌和真菌感染，以及过度的炎症反应。CGD的过度炎症不仅是感染未解决的结果，而且是炎症控制的内在缺陷所致。利用基因工程小鼠模型，我们已经确定了NADPH氧化酶可能下调炎症的两种可能机制。首先，我们已经证明，在体外和体内，NADPH氧化酶直接或间接地下调核因子-βB的激活。其次，NADPH氧化酶激活核红系2 p45相关因子2(Nrf2)，这是一个关键的氧化还原敏感途径，具有抗炎和抗肿瘤特性。我们的具体目标集中在与NADPH氧化酶如何下调炎症相关的三个相互关联的问题上：特定目标1：验证NADPH氧化酶通过氧化还原敏感地抑制IKK2活性来减弱NF-1激活的假说。特异性目的2：评价NADPH氧化酶和Nrf2在调节炎症中的相互作用。具体目的3：验证中性粒细胞来源的NADPH氧化酶来源的ROI在过继转移后将调节邻近细胞中的NF-βB和Nrf2信号并减轻CGD小鼠炎症的假说。公共卫生相关性：慢性肉芽肿性疾病(CGD)是一种罕见的遗传性HE NADPH氧化酶疾病，是宿主抵御微生物病原体的关键组成部分。我们的提案将评估NADPH氧化酶调节炎症的机制，这对我们理解CGD非常重要，并将与炎症障碍和癌症等病理条件广泛相关。

DESCRIPTION (provided by applicant): Chronic granulomatous disease (CGD) is a rare inherited disorder of the NADPH oxidase complex in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs). CGD is characterized by recurrent life-threatening bacterial and fungal infections and by excessive inflammatory responses. Excessive inflammation in CGD is not solely the result of unresolved infection, but results from an intrinsic defect in the control of inflammation. Using genetically engineered mouse models, we have identified two possible mechanisms by which NADPH oxidase may downregulate inflammation. First, we have shown that NADPH oxidase, directly or indirectly, downregulates NF-?B activation in vitro and in vivo. Second, NADPH oxidase activates nuclear erythroid 2 p45 related factor 2 (Nrf2), a key redox-sensitive pathway with anti- inflammatory and anti-neoplastic properties. Our specific aims are focused on three inter-related questions related to how NADPH oxidase downregulates inflammation: Specific aim 1: To test the hypothesis that NADPH oxidase attenuates NF-: activation by redox-sensitive suppression of IKK2 activity. Specific aim 2: To evaluate the interaction of NADPH oxidase and Nrf2 in regulating inflammation. Specific aim 3: To test the hypothesis that NADPH oxidase-derived ROIs from neutrophils will modulate NF-??B and Nrf2 signaling in neighboring cells and reduce inflammation in CGD mice following adoptive transfer. Public Health Relevance: Chronic granulomatous disease (CGD) is a rare inherited disorder of the he NADPH oxidase, a critical component of host defense against microbial pathogens. Our proposal will evaluate mechanisms by which NADPH oxidase regulates inflammation that will be important to our understanding of CGD, and will be broadly relevant to pathologic conditions, such as inflammatory disorders and cancer.