Acute lung injury (ALI) most commonly occurs after severe bacterial infections such as pneumonia or sepsis. A clear impediment to successful ALI therapy resides in a complex disease course often characterized by an initial burst in host inflammation from pro- inflammatory mediators resulting in extensive tissue injury;a second phase of immunosuppression ensues that poses risks for secondary bacterial infections. IL-1, generated by the inflammasome and invasive bacterial infections both contribute to disease pathobiology and illness severity. The mechanistic platform of this project resides on our discovery of a unique molecular model of inflammation whereby a relatively new protein, Fbxo3, potently triggers IL-1 release from human inflammatory cells after bacterial infection by destabilizing a crucial inflammasome inhibitor, Fbxl2. By targeting the ApaG molecular signature present in both host Fbxo3 and many bacteria, we developed a first-in-class genus of small molecule inhibitors that display dual anti-inflammatory and anti-bacterial activity in murine ALI models. Hence, in this application we will first elucidate how bacterial pathogens transcriptionally activate Fbxo3, allowing the protein to eliminate an inflammasome inhibitor, Fbxl2 (Aim 1). We will specifically elucidate how Fbxl2 targets the NALP7 inflammasome. Next we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary anti-inflammatory and anti-bacterial properties in ALI models (Aim 2). These studies will provide a new mechanistic pathway of innate immunity that will serve as a basis to fulfill an unmet therapeutic need in subjects with altered immune responses during critical illness.
Acute lung injury (ALI) is a major cause of morbidity and mortality in the US and evidence suggests that patients die from overwhelming inflammation or immunosuppression, the latter making people prone to bacterial infections. Lung inflammation is caused from the release of proteins, called cytokines. We have discovered a new model of inflammation in subjects with ALI. This discovery led us to develop a new family of drugs that reduce cytokine-driven inflammation but are also anti- bacterial. This discovery fulfills an unmet need in ALI therapy.
|Chen, Yan; Li, Jin; Dunn, Sarah et al. (2014) Histone deacetylase 2 (HDAC2) protein-dependent deacetylation of mortality factor 4-like 1 (MORF4L1) protein enhances its homodimerization. J Biol Chem 289:7092-8|
|Zou, Chunbin; Mallampalli, Rama K (2014) Regulation of histone modifying enzymes by the ubiquitin-proteasome system. Biochim Biophys Acta 1843:694-702|
|Weathington, Nathaniel M; Snavely, Courtney A; Chen, Bill B et al. (2014) Glycogen synthase kinase-3? stabilizes the interleukin (IL)-22 receptor from proteasomal degradation in murine lung epithelia. J Biol Chem 289:17610-9|
|Chen, Bill B; Coon, Tiffany A; Glasser, Jennifer R et al. (2014) E3 ligase subunit Fbxo15 and PINK1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia. Cell Rep 7:476-87|
|Han, SeungHye; Mallampalli, Rama K (2014) Sizing up surfactant synthesis. Cell Metab 20:195-6|
|Weathington, Nathaniel M; Mallampalli, Rama K (2014) Emerging therapies targeting the ubiquitin proteasome system in cancer. J Clin Invest 124:6-12|
|Liu, Yuan; Mallampalli, Rama K (2014) Decoding the growth advantage of hypoxia-sensitive lung cancer. Am J Respir Crit Care Med 190:603-5|
|Agassandian, Marianna; Mallampalli, Rama K (2013) Surfactant phospholipid metabolism. Biochim Biophys Acta 1831:612-25|
|Chen, Bill B; Coon, Tiffany A; Glasser, Jennifer R et al. (2013) A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation. Nat Immunol 14:470-9|
|Weathington, Nathaniel M; Mallampalli, Rama K (2013) New insights on the function of SCF ubiquitin E3 ligases in the lung. Cell Signal 25:1792-8|
Showing the most recent 10 out of 24 publications