Influenza is a yearly epidemic that causes up to 500,000 global deaths annually. Most patientsdie 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 noveltherapies for this deadly disease. Our preliminary data demonstrate that syndecan-1, a cellsurface proteoglycan, regulates lung inflammation and reduces morbidity and mortality in miceafter infection. Moreover, our data indicate that syndecan-1 restricts lung injury after influenzainfection by limiting apoptosis in the airway epithelium. Our findings also show that syndecan-1activates AKT, a pro-survival signal that can inhibit apoptosis. The central hypothesis for ourproposal is that syndecan-1 is a pro-survival signal that attenuates epithelial apoptosis afterinfluenza infection to limit lung injury. We will evaluate the mechanisms by which syndecan-1regulates various apoptotic pathways. Additionally, we will investigate whether syndecan-1suppresses 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 noveltherapeutics 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Caler, Elisabet V
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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