The acute respiratory distress syndrome (ARDS) is most commonly due to severe bacterial infection, including pneumonia. Despite decades of intense study, mortality rates for ARDS are still very high and yet newer therapeutic strategies based on fundamentally novel molecular-pathophysiologic-driven models have not emerged. This PPG application is based on our seminal discovery that a critical mitochondrial-specific lipid, cardiollpin, profoundly produces ARDS-like features when released into the extracellular environment (Nat. Med. 2010). The overall conceptual model underlying this Program is that cardiollpin is a new lipidomic associated molecular pattern encoding bacterial-like molecular signatures that is normally masked by its compartmentalization within the inner mitochondrial membrane of mammalian cells. However, in our preliminary data suggest that in pneumonia models there occur seminal events whereby cardiollpin is exposed into the extracellular environment through its dysregulated biosynthesis (Project 1) or oxidative transmigration (Project 2) from mitochondria in epithelia resulting in severe adverse consequences for immune suppressor activities of myeloid cells (Project 3). Thus, the overall hypothesis is that cardiollpin elicits differential efects on pulmonary homeostasis in ARDS that are cell specific and highly compartmentalized. To execute this Program, we have assembled a team of world-class leaders with complementary expertise to synergistically investigate mechanisms that modulate availability cardiollpin and its role in mitochondrial integrity, epithelial apoptosis, and innate immune function. To evaluate the hypothesis, investigators will employ state-of-art molecular, cell-based, and lipidomic tools that will be translated to complementary in vivo models of lung injury and analysis in human subjects with ARDS. The Program will be supported by highly interactive Cores with expertise in oxidative lipidomics, animal and human repository services, and bioimaging. Execution of these studies will provide a paradigm-changing conceptual model for ARDS pathogenesis that serves as a basis for therapeutic intervention and providing a new and sustained field of scientific inquiry in lung biology.

Public Health Relevance

ARDS is most commonly due to severe bacterial infection, including pneumonia. Despite decades of intense study, mortality rates for ARDS are still very high and yet newer therapeutic strategies based on fundamentally novel molecular-pathophysiologic-driven models have not emerged. This PPG application is based on our seminal discovery that a critical mitochondrial-specific lipid, cardiolipin, profoundly produces ARDS-like features when released into the extracellular environment.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HL114453-04
Application #
9204414
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Harabin, Andrea L
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
McKelvey, Alison C; Lear, Travis B; Dunn, Sarah R et al. (2016) RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity. Elife 5:
Nan, Ling; Jacko, Anastasia M; Tan, Jiangning et al. (2016) Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFβ-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis. Sci Rep 6:33116
Liu, Yuan; Mallampalli, Rama K (2016) Small molecule therapeutics targeting F-box proteins in cancer. Semin Cancer Biol 36:105-19
Lear, Travis; McKelvey, Alison C; Rajbhandari, Shristi et al. (2016) Ubiquitin E3 ligase FIEL1 regulates fibrotic lung injury through SUMO-E3 ligase PIAS4. J Exp Med 213:1029-46
Harris, Leonard A; Hogg, Justin S; Tapia, José-Juan et al. (2016) BioNetGen 2.2: advances in rule-based modeling. Bioinformatics 32:3366-3368
Morel, Penelope A; Lee, Robin E C; Faeder, James R (2016) Demystifying the cytokine network: Mathematical models point the way. Cytokine :
Singamsetty, Srikanth; Shah, Faraaz Ali; Guo, Lanping et al. (2016) Early initiation of low-level parenteral dextrose induces an accelerated diabetic phenotype in septic C57BL/6J mice. Appl Physiol Nutr Metab 41:12-9
Mao, Gaowei; Qu, Feng; St Croix, Claudette M et al. (2016) Mitochondrial Redox Opto-Lipidomics Reveals Mono-Oxygenated Cardiolipins as Pro-Apoptotic Death Signals. ACS Chem Biol 11:530-40
Tejero, Jesús; Kapralov, Alexandr A; Baumgartner, Matthew P et al. (2016) Peroxidase activation of cytoglobin by anionic phospholipids: Mechanisms and consequences. Biochim Biophys Acta 1861:391-401
Buland, Justin R; Wasserloos, Karla J; Tyurin, Vladimir A et al. (2016) Biosynthesis of oxidized lipid mediators via lipoprotein-associated phospholipase A2 hydrolysis of extracellular cardiolipin induces endothelial toxicity. Am J Physiol Lung Cell Mol Physiol 311:L303-16

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