Role of NADPH Oxidase in Regulating Inflammation

NADPH 氧化酶在调节炎症中的作用

• 批准号: 8012832
• 负责人: Brahm H Segal
• 金额: $ 42.64万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012832
• 关键词: Acute; Adoptive Transfer; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attenuated; Bacterial Infections; Biological Products; Bone Marrow; CD14 gene; CSF3 gene; Catalytic Domain; Cell Nucleus; Cell Wall; Cells; Chronic Granulomatous Disease; Complex; Cysteine; Cytoplasmic Granules; Defect; Disease; Dissociation; Enzymes; Erythroid; Feedback; Genetically Engineered Mouse; Host Defense; Imidazole; In Vitro; Inborn Genetic Diseases; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-17; Lead; Life; Ligands; Ligation; Lipopolysaccharides; Lung; Lung Inflammation; Macrophage-1 Antigen; Malignant Neoplasms; Modeling; Mus; Mycoses; NADPH Oxidase; Nuclear; Oxidants; Oxidation-Reduction; Pathologic; Pathway interactions; Peptide Hydrolases; Phagocytes; Play; Property; Recurrence; Role; Signal Transduction; Superoxides; TNF gene; Testing; Therapeutic; Toll-Like Receptor 2; Toll-like receptors; Toxin; Zymosan; attenuation; base; caspase-3; chemokine; cytokine; dectin 1; environmental agent; in vivo; inhibitor/antagonist; macrophage; microbial; mouse model; neoplastic; neutrophil; novel; oxidation; pathogen; public health relevance; receptor; response; therapeutic target; toll-like receptor 4; tumor; ultraviolet irradiation

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.

描述（由申请方提供）：慢性肉芽肿病（CGD）是一种罕见的NADPH氧化酶复合物遗传性疾病，其中吞噬细胞在产生超氧阴离子和下游反应性氧化剂中间体（ROI）方面存在缺陷。CGD的特征在于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中的过度炎症不仅仅是未解决的感染的结果，而是由炎症控制的内在缺陷引起的。使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，我们已经表明，NADPH氧化酶，直接或间接，下调NF-？体外和体内B活化。其次，NADPH氧化酶激活核红细胞2 p45相关因子2（Nrf 2），这是一种具有抗炎和抗肿瘤特性的关键氧化还原敏感性途径。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：具体目标1：检验NADPH氧化酶通过氧化还原敏感性抑制IKK 2活性而减弱NF-κ B激活的假设。具体目标2：评估NADPH氧化酶和Nrf 2在调节炎症中的相互作用。具体目标3：检验中性粒细胞的NADPH氧化酶衍生的ROI将调节NF-κ B的假设。B和Nrf 2信号传导在相邻细胞中，并减少过继转移后CGD小鼠中的炎症。公共卫生相关性：慢性肉芽肿病（CGD）是一种罕见的遗传性疾病的NADPH氧化酶，一个重要组成部分的主机防御微生物病原体。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，并且与病理条件（如炎症性疾病和癌症）广泛相关。