A central challenge for PENTACON in identifying molecular-level causes of NSAID-specificity with respect to efficacy vs. adverse effects is the integrative computational modeling of the activity of the diverse cellular components that are perturbed upon NSAID administration. It is in these two cores that integrate our approaches to systems biology and modeling. In the Systems, Modeling and Computation Cores we describe how PENTACON will produce an outcome that is greater than the sum its component parts. We will use network-based discrete and dynamic computational models to integratively model behavior and functional conservation of diverse biomolecules, accounting for cell-lineage and environmental effects in the context of genomic and environmental variation. We are aware of the levels of complexity in this system that we may not be directly modeling. Indeed, some elements may even violate our assumptions, for example splice variants and discrete impacts of the epigenome. We address these challenges through (1) a combination of diverse approaches, including exploratory studies (such as for microbiome data) and (2) directed modeling efforts and close iteration of modeling and experimental verification with quantitative functional outputs that translate directly to humans. We will also adopt a flexible approach, updating the modeling approaches to information that emerges from our analyses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54HL117798-01
Application #
8126760
Study Section
Special Emphasis Panel (ZGM1-PPBC-0 (GL))
Project Start
2012-08-01
Project End
2017-05-31
Budget Start
2012-08-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$311,359
Indirect Cost
$70,306
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Dong, Liang; Zou, Hechang; Yuan, Chong et al. (2016) Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis. J Biol Chem 291:4069-78
Bender, Gunes; Schexnaydre, Erin E; Murphy, Robert C et al. (2016) Membrane-dependent Activities of Human 15-LOX-2 and Its Murine Counterpart: IMPLICATIONS FOR MURINE MODELS OF ATHEROSCLEROSIS. J Biol Chem 291:19413-24
Zemski Berry, Karin A; Murphy, Robert C (2016) Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages. Chem Res Toxicol 29:1355-64
Mazaleuskaya, Liudmila L; Lawson, John A; Li, Xuanwen et al. (2016) A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood. JCI Insight 1:
Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan et al. (2016) Radiation therapy generates platelet-activating factor agonists. Oncotarget 7:20788-800
Martin, Sarah A; Brash, Alan R; Murphy, Robert C (2016) The discovery and early structural studies of arachidonic acid. J Lipid Res 57:1126-32
FitzGerald, Garret A (2016) ImPRECISION: Limitations to Interpretation of a Large Randomized Clinical Trial. Circulation :
Guo, Lili; Worth, Andrew J; Mesaros, Clementina et al. (2016) Diisopropylethylamine/hexafluoroisopropanol-mediated ion-pairing ultra-high-performance liquid chromatography/mass spectrometry for phosphate and carboxylate metabolite analysis: utility for studying cellular metabolism. Rapid Commun Mass Spectrom 30:1835-45
Xiang, Yaozu; Hwa, John (2016) Regulation of VWF expression, and secretion in health and disease. Curr Opin Hematol 23:288-93
Dong, Liang; Zou, Hechang; Yuan, Chong et al. (2016) Interactions of 2-O-arachidonylglycerol ether and ibuprofen with the allosteric and catalytic subunits of human COX-2. J Lipid Res 57:1043-50

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