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.
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.
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|Long, Huaicong; O'Connor, Brian P; Zemans, Rachel L et al. (2014) The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One 9:e93550|
|Leissinger, Mary; Kulkarni, Ritwij; Zemans, Rachel L et al. (2014) Investigating the role of nucleotide-binding oligomerization domain-like receptors in bacterial lung infection. Am J Respir Crit Care Med 189:1461-8|
|Aschner, Yael; Zemans, Rachel L; Yamashita, Cory M et al. (2014) Matrix metalloproteinases and protein tyrosine kinases: potential novel targets in acute lung injury and ARDS. Chest 146:1081-91|
|Zemans, Rachel L; McClendon, Jazalle; Aschner, Yael et al. (2013) Role of *-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 304:L415-27|
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|Zemans, Rachel L; Stream, Amanda R; Musani, Ali I et al. (2012) A 46-year-old man with seizures, brain lesions, and pulmonary infiltrates. Chest 141:265-9|
|Matthay, Michael A; Zemans, Rachel L (2011) The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol 6:147-63|
|Schmidt, Eric P; Lee, Warren L; Zemans, Rachel L et al. (2011) On, around, and through: neutrophil-endothelial interactions in innate immunity. Physiology (Bethesda) 26:334-47|
|Zemans, Rachel L; Briones, Natalie; Campbell, Megan et al. (2011) Neutrophil transmigration triggers repair of the lung epithelium via beta-catenin signaling. Proc Natl Acad Sci U S A 108:15990-5|