Following injury, epithelial cells initiate a programmed series of coordinated responses, such proliferation, migration, differentiation, and matrix remodeling, to restore tissue integrity. Matrilysin (MMP-7) is expressed by migrating epithelial cells in injured airway and alveoli and its activity is essential reepithelialization. In both in vivo and ex vivo models, airway wounds do not repair in matrilysin-null mice. In addition, matrilysin controls neutrophil recruitment into the alveolar space following lung injury by directing compartmentalization of specific chemokines via shedding the ectodomain of syndecan-1, an abundant surface heparan sulfate proteoglycan. In matrilysin-null mice, syndecan-1 ectodomains are not shed response to injury. The hypothesis of this project is that matrilysin docks to and then directly cleaves ectodomain of syndecan-1 and that cleavage of syndecan-1 is required for epithelial migration and repair. In several cell-based models, the presence of intact syndecan-1 represses migration, whereas shedding correlates with movement. In addition, via lateral association, the cytoplasmic domain of intact syndecan- inhibits integrin activity, and we propose that ectodomain shedding would permit cell-matrix interactions needed for migration.
For Aim 1, rnurine and human models will be used to map the cleavage syndecan-1 ectodomain and to demonstrate that matrilysin cleaves this proteoglycan and to generate matrilysin-resistant syndecan-1 knock-in mice. The function of syndecan-1 shedding in regulating migration and adhesion to specific matrices via specific integrins will be addressed under Aim hypothesis that matrilysin docks to syndecan-1 and that this association leads to zymogen activation under Aim 3. These studies will demonstrate how matrilysin functions in lung repair.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Washington University
Saint Louis
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Byers, Derek E; Wu, Kangyun; Dang-Vu, Geoffrey et al. (2018) Triggering Receptor Expressed on Myeloid Cells-2 Expression Tracks With M2-Like Macrophage Activity and Disease Severity in COPD. Chest 153:77-86
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Gharib, Sina A; Edelman, Jeffery D; Ge, Lingyin et al. (2015) Acute cellular rejection elicits distinct microRNA signatures in airway epithelium of lung transplant patients. Transplant Direct 1:
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Holtzman, Michael J; Byers, Derek E; Alexander-Brett, Jennifer et al. (2014) The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14:686-98
Holtzman, Michael J; Byers, Derek E; Brett, Jennifer-Alexander et al. (2014) Linking acute infection to chronic lung disease. The role of IL-33-expressing epithelial progenitor cells. Ann Am Thorac Soc 11 Suppl 5:S287-91
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Byers, Derek E; Alexander-Brett, Jennifer; Patel, Anand C et al. (2013) Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J Clin Invest 123:3967-82
Chen, Peter; Edelman, Jeffrey D; Gharib, Sina A (2013) Comparative evaluation of miRNA expression between in vitro and in vivo airway epithelium demonstrates widespread differences. Am J Pathol 183:1405-1410

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