REGULATION AND FUNCTION OF EC-SOD

EC-SOD的调节和功能

• 批准号: 6654859
• 负责人: RODNEY J FOLZ
• 金额: $ 30.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654859
• 关键词: bronchopulmonary dysplasia; enzyme mechanism; genetic regulatory element; genetically modified animals; isozymes; laboratory mouse; lung; lung development; molecular pathology; morphometry; newborn animals; oxidative stress; protein localization; pulmonary circulation; recombinant proteins; respiratory epithelium; superoxide dismutase; vascular smooth muscle

Extracellular superoxide dismutase (EC-SOD) is the most abundant extracellular antioxidant enzyme in the lung. However its biological role in both the neonatal and adult lung, during health and disease, is poorly understood. In the lung, EC-SOD has been primarily localized to alveolar type II epithelial cells as well as to pulmonary vascular smooth muscle. Thus, EC-SOD has positioned itself to likely play an important role in both pulmonary vascular biology as well as in alveolar epithelial homeostasis. We have previously shown that the mouse lung has the highest tissue expression of EC-SOD. Further enhancing EC-SOD levels using transgenic mice overexpressing human EC-SOD in type II alveolar epithelial cells resulted in attenuation of lung injury in models of oxidative stress. The long-term goal of this project is to understand the basic biochemistry and molecular pathobiology and regulation of EC-SOD in the lung. Towards this goal, we have proposed the following specific aims: (1) Identify, map, and functionally characterize the murine EC-SOD promoter and transcriptional regulatory elements. (2) Characterize the distribution and differential gene expression pattern of various EC-SOD mRNA isoforms under normal and oxidative stress conditions. (3) Critically evaluate EC-SOD expression during lung development. (4) Test the hypothesis that reduced EC-SOD expression in premature lungs predisposes to the development of hyperoxic-induced bronchopulmonary dysplasia and that overexpression protects against its development. We expect that data derived from these studies will further our understanding of basic mechanisms involved in regulating EC-SOD expression in the lung and underlie the basis for rational development of future studies utilizing transgenic mice technology, targeted against pulmonary and cardiovascular diseases.

细胞外超氧化物歧化酶（EC-SOD）是肺中含量最多的细胞外抗氧化酶。然而，在健康和疾病期间，其在新生儿和成人肺部的生物学作用尚不清楚。在肺中，EC-SOD主要局限于肺泡II型上皮细胞和肺血管平滑肌。因此，EC-SOD定位于可能在肺血管生物学和肺泡上皮稳态中发挥重要作用。我们之前的研究表明，小鼠肺中EC-SOD的组织表达最高。利用过表达人EC-SOD的转基因小鼠进一步提高II型肺泡上皮细胞中EC-SOD的水平，导致氧化应激模型肺损伤的减弱。本项目的长期目标是了解肺组织中EC-SOD的基本生物化学和分子病理生物学及其调控。为了实现这一目标，我们提出了以下具体目标：(1)鉴定、定位和功能表征小鼠EC-SOD启动子和转录调控元件。(2)表征正常和氧化应激条件下各种EC-SOD mRNA亚型的分布和差异基因表达模式。(3)严格评估肺发育过程中EC-SOD的表达。(4)验证过早肺中EC-SOD表达降低易导致高氧诱导的支气管肺发育不良，而过表达可防止其发展的假设。我们期望从这些研究中获得的数据将进一步加深我们对调节肺中EC-SOD表达的基本机制的理解，并为利用转基因小鼠技术合理开发针对肺部和心血管疾病的未来研究奠定基础。