Role of Beta-catenin in Epithelial Repair in Acute Lung Injury

描述（由申请人提供）：该资助旨在研究转运过程中PMN与上皮细胞相互作用激活肺上皮细胞中2-catenin依赖性信号通路的机制，以及这些通路在上皮修复中的重要性。我们将确定触发上皮2-连环蛋白激活的信号通路，包括PMN弹性酶裂解E-cadherin。我们将在体外和基因靶向小鼠ALI模型中确定2- catenin激活促进PMN迁移诱导的上皮损伤修复的机制。

DESCRIPTION (provided by applicant): This grant seeks to investigate the mechanisms by which PMN interactions with epithelial cells during transmigration activate 2-catenin-dependent signaling pathways in lung epithelial cells and the importance of these pathways in epithelial repair. We will determine the signaling pathways that trigger epithelial 2-catenin activation including E-cadherin cleavage by PMN elastase. We will determine the mechanisms by which 2- catenin activation promotes repair of epithelial injury induced by PMN transmigration in vitro and in murine models of ALI using gene-targeted mice. PUBLIC HEALTH RELEVANCE: Acute Lung Injury (ALI) is a frequent complication in critically ill patients that is responsible for significant morbidity, mortality, and the expenditure of > $50 billion annually in health care costs. To date, aside from lung protective mechanical ventilation strategies and supportive care, there are no specific therapies for ALI and mortality rates remain unacceptably high (20-50%). Recovery from ALI is dependent on repair of the cells that line the air sacs of the lung (epithelial cells). We have discovered that 2-catenin, an intracellular protein, promotes repair of these lining cells. We propose to study how this beneficial effect is exerted with the goal of identifying specific targets for therapies to speed recovery from this devastating disorder.