期刊
TOXICOLOGY IN VITRO
卷 24, 期 1, 页码 310-318出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2009.08.008
关键词
Apoptosis; Oxidative stress; Gene expression knockdown; Human druggable genome; Alveolar destruction; Chronic lung disease
类别
资金
- GSK
Chronic obstructive pulmonary disease (COPD) is an increasing health problem primarily associated with cigarette smoking, and one of the leading causes of morbidity and mortality worldwide. Despite recent advances in understanding the pathogenesis of the disease, overall patient outcome remains poor with limited therapeutic intervention. Chronic inflammation, an imbalance between proteolytic and anti-proteolytic activities (leading to lung parenchyma destruction) and excessive oxidative stress contribute to COPD pathophysiology. Oxidative stress-triggered apoptosis of alveolar structural cells, including epithelial cells, may be an important event in the development of COPD. In this study, we developed a cell-based oxidative stress-induced apoptosis assay and performed a high-throughput screen (HTS) using a human druggable genome siRNA library. Our results have identified potential novel pathways (e.g. unfolded protein response, proteosomal activity) and targets (e.g. MAP3K14, HMGB2) that regulate the response of lung epithelial cells to oxidative stress. This assay has proven to be a useful tool for the identification of potential new therapeutic targets for lung disease. (C) 2009 Elsevier Ltd. All rights reserved.
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