2006 Progress Report: Hepatocyte Metabolism Model for Xenobiotics
EPA Grant Number: R832721C002Subproject: this is subproject number 002 , established and managed by the Center Director under grant R832721
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: New Jersey Research Center for Environmental Bioinformatics and Computational Toxicology
Center Director: Welsh, William J.
Title: Hepatocyte Metabolism Model for Xenobiotics
Investigators: Ierapetritou, Marianthi , Androulakis, Ioannis
Current Investigators: Ierapetritou, Marianthi , Androulakis, Ioannis , Floudas, Christodoulos , Georgopoulos, Panos G. , Rabitz, Herschel , Tong, Weida , Welsh, William J.
Institution: Rutgers University
Current Institution: Princeton University , Rutgers University , U.S. Food and Drug Administration , University of Medicine and Dentistry of New Jersey
EPA Project Officer: Mustra, David
Project Period: October 1, 2005 through September 30, 2010
Project Period Covered by this Report: October 1, 2005 through September 30, 2006
RFA: Computational Toxicology: Environmental Bioinformatics Research Center (2004)
Research Category: Computational Toxicology
Description:
Objective:The aims of this project have not changed from the original application; original objectives for the report period have been met. However, specific collaborative case studies have been defined during the report period to facilitate testing and evaluating of the accomplishment of these aims.
Progress Summary:- Applied and customized metabolic engineering tools in conjunction with mathematical programming to identify important pathways within the overall hepatocyte metabolism. Tools used include metabolic flux analysis, logic programming, advanced optimization, elementary mode analysis, and extreme pathway analysis.
- Extended the hepatocyte network to include pathways responsible for the metabolism of toxic substances. As a well-studied case study, the pathways of acetaminophen were included along with the relevant metabolic paths responsible for the effects of alcohol.
- Studied androgenesis-related effects associated with dibutyl phthalate (DBP) exposures through analysis of microarray expression data from rat testis. Identified critical gene expression motifs, associated gene ontology functions, and maximally affected pathways and performed cross-species extrapolation conservation of protein sequences between rat and human.
Results to Date
- Developed a mixed integer linear optimization approach that enables the identification of important pathways in a complex metabolic network.
- Developed network decomposition principles and analysis tools to enable the consideration of large scale networks.
- Extended the basic hepatic metabolism to incorporate the main pathways responsible for detoxification. As a case study, a cetaminophen was used since there are suitable data available to study the interactions of the main pathways in liver metabolism and the effects of other parameters such as alcohol and fasting.
- Developed novel methods for analysis of temporal gene expression data. Developed novel methods for quantifying pathway activities and cross-species (rat/human) extrapolation of protein conservation.
- Incorporation of regulatory rules within the analysis of metabolic networks to restrict the alternative solutions and result in better estimation of internal fluxes that cannot be measured. This can be achieved utilizing logic-based programming.
- Investigation of different case studies involving toxic substances to determine and evaluate the alternative pathways involved in liver detoxification and analyze the dependence to central liver metabolism under different conditions.
- Extension of methodologies for evaluating significant pathways affected by DBP exposure and consistently evaluat ion of the level of cross-species conservation of important proteins. Design study for obtaining relevant time-course expression data.
No journal articles submitted with this report: View all 8 publications for this subproject
Supplemental Keywords:computational toxicology, toxicogenomics, bioinformatics, toxicoinformatics, proteomics, metabonomics, physiomics, cytomics, genomics, transcriptomics, enviroinformatics, cheminformatics, biologically based dose-response modeling, cross-species extrapolation, risk assessment,
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ENVIRONMENTAL MANAGEMENT, Geographic Area, Scientific Discipline, Health, Risk Assessment, Biology, Risk Assessments, Biochemistry, Environmental Monitoring, State, exposure assessment, biochemical research, chemical composition, ecological risk assessment, toxicologic assessment, bioinformatics, human health risk, biopollution, toxicology, environmental risks, risk, computational toxicology, New Jersey (NJ)
Relevant Websites:
Progress and Final Reports:
Original Abstract
2007 Progress Report
Main Center Abstract and Reports:
R832721 New Jersey Research Center for Environmental Bioinformatics and Computational Toxicology
Subprojects under this Center:
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R832721C001 Development and Application of the DORIAN (Dose-Response Information Analysis) System
R832721C002 Hepatocyte Metabolism Model for Xenobiotics
R832721C003 Development of Computational Tools for Optimal Identification of Biological Networks
R832721C004 Cheminformatics Tools for Toxicant Characterization
R832721C005 Optimization Tools for In Silico Structural Proteomics