Reactive oxygen species and anti-oxidants in ALI

ALI 中的活性氧和抗氧化剂

• 批准号: 7418361
• 负责人: Aron B. FISHER
• 金额: $ 242.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418361
• 关键词: Reactive; oxygen; species; anti; oxidants

DESCRIPTION (provided by applicant): This application represents a multidisciplinary effort to investigate the mechanisms for lung defense against oxidative stress. The hypothesis for the program is that generation of reactive oxygen species (ROS) in patients at risk plays a critical role in the initiation of lung damage leading to a cascade of events that culminates in the syndrome of acute lung injury (ALl). The major focus will be on antioxidant enzymatic protection with special focus on a newly described lung antioxidant enzyme, peroxiredoxin 6 (Prdx 6). Results generated during a period of R-01 support to study this enzyme indicate that Prdx 6 can reduce phospholipid hydroperoxides which provides a basis for protection against oxidant stress through reversal of membrane lipid peroxidation. We will utilize mouse models of altered Prdx 6 expression to determine the role of this enzyme in antioxidant defense, will evaluate control of Prdx 6 expression under oxidant stress, and will characterize the biochemical requirements for enzymatic activity with respect to binding and catalysis of phospholipid hydroperoxides. We will identify functional polymorphisms in specific antioxidant genes that are associated with an increased risk of ALl among patients with major trauma. The functional significance of the polymorphisms will be determined by analysis of the promoter region, if relevant, or expression of the mutant protein. We will employ physical, mass spectrometric, and proteomic techniques to characterize oligomedzation and oxidative modification of Prdx 6 as well as to determine the effects of Prdx 6 expression levels on oxidative modification of other lung proteins dudng oxidative stress. We will also search for changes in blood proteins levels that are diagnostic of oxidative stress and development of ALl. We will investigate a novel strategy for anti-oxidant defense through use of polymer nanocarriers for delivery of antioxidant enzymes to endothelium. A major emphasis will be on the cytosolic delivery of Prdx 6. We will be supported by: 1) clinical, biostatistical and data management; 2) molecular engineering and protein preparation; and 3) cell culture and animal husbandry. This represents both basic science and translational studies that will provide new insights into antioxidant defense and potential mechanistic-based therapies for ROS-mediated ALl.

描述（由申请人提供）： 该应用代表了研究肺防御氧化应激的机制的多学科努力。该计划的假设是，处于危险的患者中的活性氧（ROS）的产生在开始肺损伤的开始中起着至关重要的作用，导致一系列事件导致急性肺损伤综合征（ALL）。主要重点将放在抗氧化剂酶保护上，特别关注新描述的肺抗氧化酶，过氧蛋白6（PRDX 6）。在研究该酶的R-01支持期间产生的结果表明，PRDX 6可以减少磷脂氢过氧化物，从而通过逆转膜脂质过氧化为防御氧化应激提供了基础。我们将利用改变的PRDX 6表达的小鼠模型来确定该酶在抗氧化剂防御中的作用，将评估对氧化应激下PRDX 6表达的控制，并将表征酶活性在磷脂和磷脂液过氧化物的结合和催化方面的生化性要求。我们将在特定的抗氧化剂基因中确定与大创伤患者所有人的风险增加有关的功能多态性。多态性的功能意义将通过分析启动子区域（如果相关）或突变蛋白的表达来确定。我们将采用物理，质谱和蛋白质组学技术来表征PRDX 6的寡聚化和氧化修饰，并确定PRDX 6表达水平对其他dudng氧化应激的其他肺蛋白的氧化修饰的影响。我们还将寻找诊断为所有人氧化应激和发育的血液蛋白水平的变化。我们将通过使用聚合物纳米载体将抗氧化酶递送到内皮的新型抗氧化剂防御策略。主要重点是PRDX 6的胞质递送。我们将得到以下方面的支持：1）临床，生物统计和数据管理； 2）分子工程和蛋白质制备； 3）细胞培养和畜牧业。这既代表了基础科学和翻译研究，又将为ROS介导的所有人提供有关抗氧化剂防御和潜在机械疗法的新见解。