The acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (All) affects 100- 200K people in the U.S. yearly leading to death in nearly 35% of patients. ARDS is characterized by neutrophilic inflammation, vascular leak, and alveolar filling with proteinaceous fluid. This Program Project Proposal (P01) focuses on elucidating the role of cardiolipin (CL) as a novel damage associated molecular pattern (DAMP-CL) and mediator of tissue damage in acute lung injury. The alveolar epithelium and innate immune system are central to the development of ARDS. The three primary projects detailed within the P01 focus on expounding cardiolipin biology in these key cell types;type II alveolar pneumocytes in Projects 1 and 2 and inflammatory cells including the recently characterized myeloid derived suppressor cell in Project 3. Core C (Animal Models and Human Sample Repository) is designed to optimize the translational exploration of the mechanisms identified in vitro in Projects 1-3 whereby cardiolipin leads to progressive cellular and subsequently tissue damage in All. The Core will serve to standardize the characterization of murine models of acute lung injury across the various projects using bacterial pathogens or hyperoxic insult as indicated. Core personnel will perform physiologic measurements for project investigators including Flexivent lung mechanics and permeability assessments along with tissue and fluid collection for dissemination to project investigators. In addition, a key component of the Core services will be to provide de-identified human tissue and fluid samples (collected via an ongoing IRB approved registry and biospecimen repository and existing Divisional tissue banks) to project investigators for verification of human relevance of novel findings from the bench or from murine models. In providing these services, Core C integrates tightly and interacts closely with all projects comprising the P01 proposal.
ARDS is a devasting disorder and despite several decades of research, few novel pathways have emerged underlying this illness. This Core will greatly facilitate examination of newer pathways studying a rare toxin, cardiolipin, and its production and elaboration from cells that profoundly alters lung stability. This Core will provide invaluable resources for animal studies of lung injury and provide human samples for toxin analysis.
|Zhao, Y; Olonisakin, T F; Xiong, Z et al. (2015) Thrombospondin-1 restrains neutrophil granule serine protease function and regulates the innate immune response during Klebsiella pneumoniae infection. Mucosal Immunol 8:896-905|
|Liu, Yuan; Mallampalli, Rama K (2014) Decoding the growth advantage of hypoxia-sensitive lung cancer. Am J Respir Crit Care Med 190:603-5|
|Yanamala, Naveena; Kapralov, Alexander A; Djukic, Mirjana et al. (2014) Structural re-arrangement and peroxidase activation of cytochrome c by anionic analogues of vitamin E, tocopherol succinate and tocopherol phosphate. J Biol Chem 289:32488-98|
|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|
|Mohammadyani, Dariush; Tyurin, Vladimir A; O'Brien, Matthew et al. (2014) Molecular speciation and dynamics of oxidized triacylglycerols in lipid droplets: Mass spectrometry and coarse-grained simulations. Free Radic Biol Med 76:53-60|
|Zou, Chunbin; Mallampalli, Rama K (2014) Regulation of histone modifying enzymes by the ubiquitin-proteasome system. Biochim Biophys Acta 1843:694-702|
|Kagan, Valerian E; Kapralov, Alexandr A; St Croix, Claudette M et al. (2014) Lung macrophages "digest" carbon nanotubes using a superoxide/peroxynitrite oxidative pathway. ACS Nano 8:5610-21|
|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|
Showing the most recent 10 out of 16 publications