Influenza is a yearly epidemic that causes up to 500,000 global deaths annually. Most patients die of respiratory failure from either a primary viral pneumonia or a secondary bacterial infection. Therefore, finding host factors that can limit the progression of lung injury may lead to novel therapies for this deadly disease. Our preliminary data demonstrate that syndecan-1, a cell surface proteoglycan, regulates lung inflammation and reduces morbidity and mortality in mice after infection. Moreover, our data indicate that syndecan-1 restricts lung injury after influenza infection by limiting apoptosis in the airway epithelium. Our findings also show that syndecan-1 activates AKT, a pro-survival signal that can inhibit apoptosis. The central hypothesis for our proposal is that syndecan-1 is a pro-survival signal that attenuates epithelial apoptosis after influenza infection to limit lung injury. We will evaluate the mechanisms by which syndecan-1 regulates various apoptotic pathways. Additionally, we will investigate whether syndecan-1 suppresses apoptosis via activation of AKT. Finally, we will identify novel syndecan-1 co- receptors that mediate its cytoprotective effect. These studies will provide a platform for novel therapeutics that can target the airway epithelium to limit lung injury after influenza infection. This work may also have broader implications on other infectious diseases (viral and non-viral) of the lungs.
Influenza is a deadly infection that has the potential for a large global burden of disease. Indeed, the 2009 pandemic highlighted many of the current deficiencies in influenza treatment (e.g., delay in vaccine production, resistance to antiviral therapy, etc.). These studies will provide a platform for novel therapeutics that can target the airway epithelium to limit lung injury after influenza infection and may have broader implications on other inflammatory diseases (viral and non-viral) of the lungs.
|Brauer, Rena; Chen, Peter (2016) Influenza leaves a TRAIL to pulmonary edema. J Clin Invest 126:1245-7|
|Ge, Lingyin; Habiel, David M; Hansbro, Phil M et al. (2016) miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways. JCI Insight 1:e90301|
|Brauer, Rena; Ge, Lingyin; Schlesinger, Saundra Y et al. (2016) Syndecan-1 Attenuates Lung Injury during Influenza Infection by Potentiating c-Met Signaling to Suppress Epithelial Apoptosis. Am J Respir Crit Care Med 194:333-44|
|Gill, Sean E; Nadler, Samuel T; Li, Qinglang et al. (2016) Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation. Am J Respir Cell Mol Biol 55:243-51|
|Brauer, Rena; Chen, Peter (2015) Influenza virus propagation in embryonated chicken eggs. J Vis Exp :|
|Grazioli, Serge; Gil, Sucheol; An, Dowon et al. (2015) CYR61 (CCN1) overexpression induces lung injury in mice. Am J Physiol Lung Cell Mol Physiol 308:L759-65|
|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:|
|Rohani, Maryam G; Pilcher, Brian K; Chen, Peter et al. (2014) Cdc42 inhibits ERK-mediated collagenase-1 (MMP-1) expression in collagen-activated human keratinocytes. J Invest Dermatol 134:1230-7|