Function of NADPH Oxidase(s) in T Lymphocytes

T 淋巴细胞中 NADPH 氧化酶的功能

• 批准号: 7263414
• 负责人: MARK S WILLIAMS
• 金额: $ 30万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263414
• 关键词: Adoptive Transfer; Affect; Angiotensin II; Antioxidants; Apoptosis; B-Lymphocytes; Biochemical; Blood Platelets; Bone Marrow; Calcium; Catalytic Domain; Cell physiology; Cells; Chronic Granulomatous Disease; Cytokine Activation; Data; Development; Ectopic Expression; Elements; Enzymes; Event; Exhibits; Family; Family member; Fas Signaling Pathway; Fibroblasts; Gene Expression; Generations; Genetic Models; Genetic Polymorphism; Homologous Gene; Host Defense; Human; Immune response; Insulin; Lead; Ligands; Ligation; MAP Kinase Gene; Mature T-Lymphocyte; Measures; Mediating; Memory Loss; Molecular; Mus; Mutation; NADPH Oxidase; Oxidases; Oxidation-Reduction; Oxidative Stress; Patients; Phagocytes; Phosphorylation; Phosphotransferases; Production; Proteins; Reactive Oxygen Species; Receptor Signaling; Regulation; Relative (related person); Reporting; Research Personnel; Role; Second Messenger Systems; Signal Transduction; Small Interfering RNA; Source; T memory cell; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Tissues; cardiovascular disorder risk; cytokine; human CYBA protein; in vivo; neutrophil cytosol factor 67K; programs; prototype; receptor; response; second messenger

DESCRIPTION (provided by applicant): The family of NADPH oxidase enzymes serve to generate reactive oxygen species (ROS). The prototype, the phagocyte-type NADPH oxidase produces large amounts of ROS that serve a host defense role. The absence or mutation of components of this oxidase (NOX2/gp91phox, p47phox, p67phox, p22phox, Rac2) results in chronic granulomatous disease (CGD). Also, polymorphisms in p22phox are associated with increased risk of cardiovascular disease. Expression of NADPH oxidase activity, however, is not restricted to phagocytes. Fibroblasts, B lymphocytes and platelets express NOX2/gp91phox protein which leads to ROS production. Recent discovery of multiple homologues of gp91phox (e.g., NOX1, NOX4, Duox1/2) has broadened the NADPH oxidase activity in "non-phagocytic" cells. In non-phagocytic cells and tissues, NOX family members produce lower levels of ROS and are predicted to participate in regulatory and signaling roles and may promote transformation. We have recently shown that T cells express a phagocyte-type NADPH oxidase, and the absence of NADPH oxidase protein components leads to a deficiency in TCR stimulated ROS generation and altered T cell responses. Functionally, T cells from NADPH oxidase- deficient mice or humans exhibited enhanced ERK activation and a relative increase in T helper type 1 cytokine secretion. Therefore, in AIM 1 we will analyze how the phagocyte NADPH oxidase is activated in T cells and assess if the TCR signals serve as "priming" signals for the oxidase. In AIM 2, we will advance our preliminary data, which suggest that T cells also express the calcium dependent, non-phagocytic oxidase Duoxl. Duoxl produces ROS early in TCR signaling and we will analyze how it is activated and its role in regulating TCR signal transduction. Finally, in AIM 3, we will investigate the how the phagocyte NADPH oxidase affects T cell development and function, including activation, apoptosis and TH1/TH2 cytokine production. We will use adoptive transfer of oxidase-deficient T cells into Rag(-/-) recipient mice to examine how the absence of NADPH oxidase activity in only the T cells affects immune responses. The results of this study will characterize the activation and potential role(s) of NADPH oxidase(s) in T cells. It will also suggest how oxidative stress affects T cell signal transduction and development and indicate how T cell function may be altered in patients lacking NADPH oxidase function.

描述（由申请人提供）：NADPH氧化酶的家族用于产生活性氧（ROS）。原型吞噬型NADPH氧化酶会产生大量的ROS，可发挥宿主防御作用。该氧化酶（NOX2/GP91Phox，p47phox，p67phox，p22phox，rac2）的成分的缺失或突变导致慢性肉芽肿性疾病（CGD）。同样，p22phox中的多态性与心血管疾病的风险增加有关。但是，NADPH氧化酶活性的表达不仅限于吞噬细胞。成纤维细胞，B淋巴细胞和血小板表达NOX2/GP91PHOX蛋白，可导致ROS产生。最近发现GP91Phox的多种同源物（例如NOX1，NOX4，DUOX1/2）已扩大了“非腺细胞”细胞中NADPH氧化酶活性。在非吞噬细胞和组织中，NOX家族成员产生较低的ROS，预计会参与调节和信号传导作用，并可能促进转化。我们最近表明，T细胞表达吞噬型NADPH氧化酶，并且不存在NADPH氧化酶蛋白成分的缺乏会导致TCR刺激的ROS产生和T细胞反应改变。在功能上，来自NADPH氧化酶缺陷或人类的T细胞表现出增强的ERK激活，T辅助1型细胞因子分泌的T辅助助手的相对增加。因此，在AIM 1中，我们将分析如何在T细胞中激活吞噬细胞NADPH氧化酶，并评估TCR信号是否用作氧化酶的“启动”信号。在AIM 2中，我们将进步我们的初步数据，这表明T细胞还表达了依赖性钙的非传染性氧化酶Duoxl。 DUOXL在TCR信号的早期产生ROS，我们将分析其激活方式及其在调节TCR信号转导中的作用。最后，在AIM 3中，我们将研究吞噬细胞NADPH氧化酶如何影响T细胞的发育和功能，包括激活，凋亡和TH1/TH2细胞因子的产生。我们将使用氧化酶缺陷型T细胞的产卵转移到抹布（ - / - ）的受体小鼠中，以检查仅在T细胞中缺乏NADPH氧化酶活性的情况如何影响免疫反应。这项研究的结果将表征NADPH氧化酶在T细胞中的激活和潜在作用。这还将表明氧化应激如何影响T细胞信号转导和发育，并指出缺乏NADPH氧化酶功能的患者如何改变T细胞功能。