Sepsis is the leading cause of death in noncoronary intensive care units in the US. A pathognomonic feature of sepsis is severe tissue injury secondary to a profound release of host cell cytokines. Activation of tumor necrosis factor receptor associated factor (TRAF) proteins is crucial to septic inflammation as these proteins link cell surface signals to cytokine release. The mechanistic platform of this proposal resides on our discovery of a unique molecular model of innate immunity for cytokine release whereby a relatively new protein, Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by destabilizing a sentinel TRAF inhibitor, Fbxl2 (Nature Immunology 14:470-9, 2013). Our pilot data indicate that Fbxo3 and TRAF proteins in circulation positively correlate with cytokine responses in septic subjects. We also identified a hypofunctional Fbxo3 human polymorphism. By targeting the prokaryotic-like Fbxo3 ApaG molecular signature, we developed a unique genus of small molecule inhibitors that lessen severity of cytokine-driven inflammation in murine models. Hence, in this application we will elucidate how Fbxo3 degrades Fbxl2 (Aim 1), test a novel chemical entity acting as a Fbxo3 ApaG inhibitor in septic models (Aim 2), and biologically characterize a Fbxo3->TRAF pathway and naturally occurring polymorphism in a prospective cohort study in subjects with sepsis (Aim 3). These studies will provide a new pathway of innate immunity that may identify subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.

Public Health Relevance

Sepsis is a major cause of morbidity and mortality in the US and evidence suggests that patients die from overwhelming systemic inflammation. This inflammation is caused from the release of proteins, called cytokines. We have discovered a new model of inflammation in subjects with sepsis. This discovery led us to develop a new family of small molecules that lessen severity of cytokine-driven inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL097376-05A1
Application #
8694679
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Harabin, Andrea L
Project Start
2009-09-30
Project End
2018-04-30
Budget Start
2014-05-07
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$412,976
Indirect Cost
$144,374
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Goetzman, Eric S; Alcorn, John F; Bharathi, Sivakama S et al. (2014) Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction. J Biol Chem 289:10668-79
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
Mallampalli, Rama K; Glasser, Jennifer R; Coon, Tiffany A et al. (2013) Calmodulin protects Aurora B on the midbody to regulate the fidelity of cytokinesis. Cell Cycle 12:663-73

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