Cellular Redox Control and Oxidant Signaling

细胞氧化还原控制和氧化信号传导

• 批准号: 6876538
• 负责人: A RICHARD WHORTON
• 金额: $ 26.95万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876538
• 关键词: NAD(P)H dehydrogenase; apoptosis; biological signal transduction; cell growth regulation; cell proliferation; enzyme activity; fibroblasts; focal adhesion kinase; free radical oxygen; gene expression; genetic regulation; growth factor receptors; hydrogen peroxide; isozymes; mitogen activated protein kinase; neoplastic cell culture for noncancer research; nitric oxide; oxidation reduction reaction; phosphatidylinositol 3 kinase; protein structure function; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Partially reduced oxygen species are reactive derivatives of molecular oxygen well characterized to participate in cellular responses generally classified as oxidative stress. While the focus in the past has been on the role of reactive oxygen species (ROS) in toxicity and disease mechanisms, it has become increasingly clear that these molecules are powerful signaling molecules employed in normal cell growth and survival. The outcome of exposure/production of ROS depends on concentration and time course such that high, bolus exposure leads to toxicity (apoptosis or necrosis) while low continuous exposure enhances cell survival and stimulates growth. Recently several lines of evidence suggest that ROS produced by NAD(P)H oxidases (NOX) function in initiation and regulation of cell signaling pathways. For example, a NOX isoform appears to be activated by receptor tyrosine kinases (EGFR, PDGF, IR) leading to H202 production and increased phosphorylation of the receptor and enhanced signaling, inhibition of NOX activity in melanoma cells by antisense to NOX4 or p22phox leads to growth inhibition, and expression of NOX1 in fibroblasts leads to a transformed phenotype and tumor formation when these cells are injected in a mouse model. Further, elevated NOX expression is associated with smooth muscle cell proliferation and commonly seen in cells derived from human cancers. The mechanism through which NOX isoforms regulate growth and survival are not known. However, studies with exogenously applied H202 would suggest activation of growth and survival (antiapoptotic) signals are important. Thus, in these studies we will test the hypothesis that cellular expression of NOX isoforms regulates growth factor receptor activity and provides antiapoptotic signals leading to cell growth and survival. To accomplish this, we will manipulate NOX levels in cells in culture and determine the effects of altered expression on growth and apoptosis and investigate the underlying cellular mechanisms.

描述（由申请人提供）：部分还原氧是分子氧的活性衍生物，其特征在于参与通常归类为氧化应激的细胞反应。虽然过去的焦点一直是活性氧（ROS）在毒性和疾病机制中的作用，但越来越清楚的是，这些分子是正常细胞生长和存活中使用的强大信号分子。ROS的暴露/产生的结果取决于浓度和时间过程，使得高剂量暴露导致毒性（细胞凋亡或坏死），而低连续暴露增强细胞存活并刺激生长。近年来，大量研究表明，由NAD（P）H氧化酶（NOX）产生的活性氧（ROS）参与了细胞信号通路的启动和调节。例如，NOX同种型似乎被受体酪氨酸激酶激活，（EGFR，PDGF，IR）导致H2 O2产生和受体磷酸化增加以及信号传导增强，通过NOX 4或p22 phox的反义抑制黑素瘤细胞中NOX活性导致生长抑制，并且当这些细胞被注射到小鼠模型中时，成纤维细胞中NOX 1的表达导致转化的表型和肿瘤形成。此外，升高的NOX表达与平滑肌细胞增殖相关，并且通常见于源自人类癌症的细胞中。NOX亚型调节生长和存活的机制尚不清楚。然而，用外源施加的H2 O2的研究表明生长和存活（抗凋亡）信号的激活是重要的。因此，在这些研究中，我们将测试的假设，细胞表达的NOX亚型调节生长因子受体的活性，并提供抗凋亡信号，导致细胞的生长和存活。为了实现这一目标，我们将操纵培养细胞中的NOX水平，并确定改变表达对生长和凋亡的影响，并研究潜在的细胞机制。