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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL120947-01
Application #
8608331
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Caler, Elisabet V
Project Start
2014-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
Fiscal Year
2014
Total Cost
$391,500
Indirect Cost
$166,500
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195