The purpose of this PPG is to determine how the alveolar epithelium alone and in coordination with inflammatory cells in the lung contributes to the development of acute lung injury. In the first cycles of this PPG, the project investigators made important discoveries, which have enhanced our understanding of the pathophysiology of acute lung injury. All of these discoveries were supported by murine models provided by this Core. Dr. Sznajder (Project 1) used mice genetically deficient in HOIL specifically in the alveolar epithelium to identify a critical role for LUBAC in the development of lung injury. Dr. Ridge (Project 2) used mice globally deficient in vimentin to show that this intermediate filament protein serves as a scaffold required for activation of the inflammasome. Dr. Chandel has used mice harboring cell specific knockouts of key metabolic proteins to demonstrate that metabolism plays a causal role in the pathogenesis of ALI. In this renewal application, all of the project investigators have designed careful gain and loss-of-function experiments that use murine genetics to target putative genes/proteins/pathways involved in the development of acute lung injury in specific cells and tissues. To examine the effects of these interventions, the project investigators have identified a need for accurate breeding and genotyping of these murine strains and the performance of reliable, reproducible and complementary measurements to determine the severity of the resulting lung injury. To accomplish these goals, the murine phenotyping core will pursue three specific aims. First, to perform breeding and genotyping of all of the murine strains, including the generation of tissue and cell type-specific knockout animals required by the project investigators. Second, to provide investigators with several well-characterized models of acute lung injury. Third, to provide quantitative, complementary measurements of lung inflammation, lung injury and lung regeneration following the induction of lung injury. This Core provides critical support to all three projects while improving the accuracy and consistency of their findings and reducing costs. It is unlikely that these benefits could be achieved outside of the structure of this PPG.
Mice are important model organisms for human disease because they allow us to identify genes and test small molecules that might be used for the development of new therapies. This Core provides project investigators with mice that lack or overexpress key genes in the lung and provides investigators with several models of acute lung injury including a precisely characterized model of the Acute Respiratory Distress Syndrome (ARDS) induced by exposure to the influenza A virus.
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