Acute Respiratory Depress Syndrome (ARDS) can be a devastating disorder and prior studies have focused mainly on its hyper-inflammatory state. However, mounting data suggest that immune suppression partakes in this disorder, the molecular mechanisms of which remain unclear. This Project investigates a unique molecular model whereby a lysine acetyltransferase termed general control of amino acid synthesis protein 5-like 2 (Gcn5l2), normally targeted for its disposal in cells by a ubiquitin E3 ligase subunit, Fbxo24, executes alveolar epithelial cell death and suppression of genes involved in innate immunity through histone modification. Our hypothesis is that Gcn5l2, normally kept in check by ubiquitin- mediated degradation, is an endotoxin-responsive executioner of innate immune suppression and epithelial cellular death in experimental ARDS. As a corollary to this hypothesis, we propose that Gcn5l2 chemical inhibition will attenuate acetyltransferase activity. Hence, in this application we will first elucidate how endotoxin increases Gcn5l2 levels by abrogating its Fbxo24 E3 ubiquitin ligase mediated proteolysis in experimental lung injury (Aim 1). We will specifically investigate how Fbxo24 targets Gcn5l2 for its degradation using complementary in vitro and in vivo genetic models and then evaluate how endotoxin abrogates molecular interaction of these partners. Next, we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary immune modulatory and cytoprotective properties in 2-hit models of immune suppression and in an ex vivo isolated human lung system (Aim 2). These studies will provide a new pathobiologic model of immune dysregulation that will serve as a platform for generating small molecule modulators that optimize epithelial cell survival and restore host defense in subjects with severe critical illness.
Acute respiratory distress syndrome (ARDS) from severe pneumonia is a devastating illness with high mortality. Most studies have investigated lung inflammation in ARDS, although many people are prone to immune suppression with impaired ability to fight infections. We have discovered a new model that may explain immune suppression in ARDS that led us to propose developing a compound that restores immune function. This discovery fulfills an unmet need in this critical illness.
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