Extracellular superoxide dismutase (EC-SOD) is the most abundant extracellular antioxidant enzyme in the lung and current studies indicates that EC-SOD plays a key role in the pathogenesis of oxidant-induced pulmonary and vascular injury and resulting inflammation. We and others have shown that EC-SOD overexpression in the lungs of mice protects the lungs against acute lung injury from hyperoxia exposure, residual oil fly ash, influenza pneumonia, hemorrhage induced lung injury, radiation pneumonitis, bleomycin-induced lung fibrosis and preserves lung development in a neonatal model of hyperoxia. In cardiovascular disease models, EC-SOD protects against ischemia-reperfusion injury, attenuates hypertension, and specific polymorphisms impart a significant increased risk for ischemic heart disease. Despite this work, the precise mechanism of EC-SOD's protective role in these disease processes remains unclear. Recently we have begun to unravel factors important in regulating EC-SOD tissue and cell-specific expression. In this competing renewal application, we will build on our most recent findings that have begun to explore molecular pathways that control EC-SOD gene expression. Based on our initial characterization of the human and mouse EC-SOD genes, we now hypothesize that EC-SOD transcriptional expression is regulated by a family of transcription factors (Ets, MZF-1, Kruppel, and Sp1/Sp3) interacting at a proximal and distal promoter element located in the 5'-untranslated region of the murine EC-SOD gene. It is further proposed that the activity of these elements is modulated by epigenetic processes including histone acetylation and methylation. To test these hypotheses, we propose 3 specific aims.
Aim 1 will examine the contribution and identification of cis-elements and trans-activating factors regulating basal and cell specific EC-SOD expression in the lung.
In Aim 2, we will identify and characterize transcription factor elements responsible for modulation of EC-SOD gene transcription.
In Aim 3 will use a novel in vivo bioluminescence imaging system to examine the functional and spatial gene expression profile utilizing the newly discovered EC-SOD proximal and distal promoter elements in transgenic mice. It is anticipated that this work will provide new insights into our understanding of molecular mechanisms involved in the regulation of EC-SOD gene expression. This could lead to novel pharmacologic strategies for augmenting endogenous EC-SOD levels in the lungs and other tissues, which would be predicted to reduce extracellular oxidative stress and attenuate lung disease processes.
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