(Provided by application) The acute respiratory distress syndrome (ARDS) affects approximately 150,000-200,000 people each year in the United States, and has an unacceptably high mortality rate. Infection with the influenza A virus (IAV) is a clinically important cause of ARDS and 20-50,000 deaths attributable to influenza infection in the US yearly, with much higher rates of mortality during pandemics. This Program Project Grant application is founded on the hypothesis that the alveolar epithelial response to injury is of crucial importance to the outcome of patients with ARDS. The project Investigators, supported by the Cores, have generated preliminary data suggesting that specific interventions at the host-virus interface early in the course of influenza A infection can prevent or reduce the severity of influenza A-induced lung injury. They have used these data to generate interrelated hypotheses that will be tested in three Projects. In Project 1, Dr. Sznajder will test the hypothesis that linear ubiquitination assembly complex (LUBAC) modulates alveolar epithelial response to hypoxia and influenza A infection and that the mild inhibition of Na,K-ATPase in the alveolar epithelium inhibits influenza A virus replication and is thus protective against IAV. In Project 2, Dr. Ridge will determine whether vimentin acts as scaffold for the assembly and activation of the NOD-like receptor-3 (NLRP3) inflammasome and whether the NOD2 protein interaction with vimentin is required for the activation of IRF3 signaling in response to influenza A virus infection. In Project 3, Dr. Chandel will determine whether changes in glucose metabolism, autophagy and mitochondrial metabolism can be manipulated in vitro and in vivo to reduce lung injury during influenza A infection. The collective focus on influenza A induced lung injury supported by collaborations with established virologist/immunologists Drs. Susanne Herold, Keith Horvath, Robert Lamb, Harris Perlman and Christian Stehlik. These projects are supported by a Cell Culture and Translational Studies Core (Core B, Drs. Ridge and Lecuona), and by a Murine Genetics and Phenotyping Core (Core C, Drs. Budinger and Perlman) and an Administrative Core (Core A, Dr. Sznajder). The Project Investigators and Core directors are leaders in the field of lung biology and have recruited several senior scientific collaborators to the field of lung disease. These projects are interactiv conceptually and programmatically, where the aggregate of the projects is greater than the sum of its parts. The project investigators and the Core leaders have designed these studies with the goal of providing short and intermediate term deliverables in the form of novel therapies to treat influenza A induced lung injury. Preliminary studies have been conducted for each of the projects and the preliminary results support the feasibility of this proposal. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: ROLE OF LUBAC AND NA K-ATPASE IN ACUTE LUNG INJURY (Sznajder, Jacob I)
The acute respiratory distress syndrome (ARDS) affects approximately 150,000-200,000 people each year in the United States, and has an unacceptably high mortality rate of ~30-40%. In this PPG, the investigators will examine the role of the lung epithelium in the development of acute lung injury following exposure to hypoxia or infection with the influenza A virus, a major cause of ARDS. Each of the Project investigators have focused their studies on finding pathways in the lung epithelium that can be targeted for the development of new therapies to treat influenza A infection and ARDS.
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