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 #
5U54HL117798-03
Application #
8689165
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
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
Ricciotti, Emanuela; Castro, Cecilia; Tang, Soon Yew et al. (2018) Cyclooxygenase-2, Asymmetric Dimethylarginine, and the Cardiovascular Hazard From Nonsteroidal Anti-Inflammatory Drugs. Circulation 138:2367-2378
Theken, Katherine N; Grosser, Tilo (2018) Weight-adjusted aspirin for cardiovascular prevention. Lancet 392:361-362
Lin, Nan; Shay, Jessica E S; Xie, Hong et al. (2018) Myeloid Cell Hypoxia-Inducible Factors Promote Resolution of Inflammation in Experimental Colitis. Front Immunol 9:2565
Li, Xinzhi; Ballantyne, Laurel L; Crawford, Mackenzie C et al. (2018) Isoform-Specific Compensation of Cyclooxygenase (Ptgs) Genes during Implantation and Late-Stage Pregnancy. Sci Rep 8:12097
Ocana, Jesus A; Romer, Eric; Sahu, Ravi et al. (2018) Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms. J Immunol 200:4004-4011
Grosser, Tilo; Naji, Ali; FitzGerald, Garret A (2018) Urinary Prostaglandin Metabolites: An Incomplete Reckoning and a Flush to Judgment. Circ Res 122:537-539
Liu, Tianyun; Ish-Shalom, Shirbi; Torng, Wen et al. (2018) Biological and functional relevance of CASP predictions. Proteins 86 Suppl 1:374-386
Hao, Huifeng; Hu, Sheng; Wan, Qing et al. (2018) Protective Role of mPGES-1 (Microsomal Prostaglandin E Synthase-1)-Derived PGE2 (Prostaglandin E2) and the Endothelial EP4 (Prostaglandin E Receptor) in Vascular Responses to Injury. Arterioscler Thromb Vasc Biol 38:1115-1124
Mazaleuskaya, Liudmila L; Salamatipour, Ashkan; Sarantopoulou, Dimitra et al. (2018) Analysis of HETEs in human whole blood by chiral UHPLC-ECAPCI/HRMS. J Lipid Res 59:564-575
Chen, Lihong; Yang, Guangrui; Zhang, Jiayang et al. (2018) Time-Dependent Hypotensive Effect of Aspirin in Mice. Arterioscler Thromb Vasc Biol 38:2819-2826

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