A central theme in this proposal is a generic experimental design that investigates NSAID responses in five model systems, yeast, human cells, fish, mice, and man (see experimental design in the Systems Pharmacology Core). Each of these model systems offers advantages to inform NSAID responses. Because yeast don't have cyclooxygenases (COXs), but do have powerful genetics, we are using them to identify the genes and networks that regulate off target effects. We propose using human cells to understand how NSAIDs regulate cell autonomous network function in multiple cell types. Zebrafish and mice are ideal model systems for studying physiology relevant to NSAID response, e.g. how NSAIDs modify pain and blood pressure. Furthermore, they are excellent systems to find modifier genes that impact NSAID action. While zebrafish have elegant forward genetic screens, the mouse is the dominant organism for reverse genetics, and we have an array of conditional knockout mice available in this grant. Our final model system, human subjects, is the bedrock on which these studies lay. We will study NSAID response in human subjects focusing on physiological parameters such as response to pain and blood pressure. Furthermore, we will investigate individual differences in these human subjects. In all systems, we will integrate genomic information with drug levels and prostanoids and unbiased (e.g. metabolomic and lipidomic) quantitative outputs reflecting drug exposure and response. Most investigation of the physiological effects of NSAIDs has focused on the role of one or a few genes in a single model system. Here we develop a 21st-century approach that studies drug response at the network level across model systems. To do this, we need common technologies. In the Molecular Profiling Core, we propose using lipidomics, metabolomics, and proteomics to study how these small molecules are metabolized, influence prostaglandin signaling, and change the expression of proteins in a variety of experimental designs. In this core, we leverage recent advances in high throughput sequencing that now enable whole genome analysis of RNA expression dynamics, chromatin modifications, microbiome regulation, and genome sequence. This is a rapidly moving area. To ensure we stay relevant, we've enlisted Eric Schadt, Chief Scientific Officer of PacBio and Professor at UCSF, who is developing third-generation technologies to address these issues.

Agency
National Institute of Health (NIH)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL117798-03
Application #
8689171
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
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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