REGULATION AND FUNCTION OF EC-SOD

细胞外超氧化物歧化酶(EC-SOD)是肺组织中含量最丰富的细胞外抗氧化酶。然而，在健康和疾病期间，它在新生儿和成人肺中的生物学作用却知之甚少。在肺组织中，EC-SOD主要定位于肺泡II型上皮细胞和肺血管平滑肌。因此，EC-SOD可能在肺血管生物学和肺泡上皮细胞动态平衡中发挥重要作用。我们之前已经证明，小鼠肺组织中EC-SOD的组织表达最高。在II型肺泡上皮细胞中过度表达人EC-SOD的转基因小鼠进一步提高了EC-SOD水平，从而减轻了氧化应激模型中的肺损伤。该项目的长期目标是了解EC-SOD在肺中的基本生物化学和分子病理生物学及其调节。为此，我们提出了以下具体目标：(1)鉴定、定位和功能鉴定小鼠EC-SOD启动子和转录调控元件。(2)研究正常和氧化应激条件下不同EC-SOD基因亚型的分布和差异基因表达模式。(3)严格评估EC-SOD在肺发育过程中的表达。(4)验证早产儿肺EC-SOD表达减少易导致高氧诱导的支气管肺发育不良的发展，以及过度表达可防止其发展的假设。我们期待从这些研究中获得的数据将进一步加深我们对调节肺内EC-SOD表达的基本机制的理解，并为未来利用转基因小鼠技术进行针对肺和心血管疾病的合理研究奠定基础。

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.