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

描述（由申请人提供）：该基金旨在研究中性粒细胞在迁移过程中与上皮细胞相互作用激活肺上皮细胞2-连环蛋白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细胞2-连环蛋白激活的信号通路，包括E-钙粘蛋白被PMN弹性蛋白酶裂解。我们将确定2- catenin激活促进体外PMN迁移诱导的上皮损伤修复的机制，并使用基因靶向小鼠建立ALI小鼠模型。 公共卫生相关性：急性肺损伤（ALI）是危重患者的常见并发症，其导致显著的发病率、死亡率和每年> 500亿美元的医疗保健费用支出。迄今为止，除了肺保护性机械通气策略和支持性护理外，没有针对ALI的特异性疗法，死亡率仍然高得不可接受（20-50%）。从ALI中恢复取决于排列在肺气囊上的细胞（上皮细胞）的修复。我们已经发现，2-连环蛋白，一种细胞内蛋白，促进这些衬里细胞的修复。我们建议研究这种有益的作用是如何发挥的，目的是确定治疗的具体目标，以加速从这种毁灭性疾病中恢复。

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.