Grantee Research Project Results
2007 Progress Report: Development and Application of the DORIAN (Dose-Response Information Analysis) System
EPA Grant Number: R832721C001Subproject: this is subproject number 001 , 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: Development and Application of the DORIAN (Dose-Response Information Analysis) System
Investigators: Georgopoulos, Panos G. , Welsh, William J. , Floudas, Christodoulos , Rabitz, Herschel , Androulakis, Ioannis , Ierapetritou, Marianthi , Tong, Weida
Institution: Rutgers , U.S. Food and Drug Administration , University of Medicine and Dentistry of New Jersey , Princeton University
Current Institution: Rutgers , Princeton University , U.S. Food and Drug Administration , University of Medicine and Dentistry of New Jersey
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 2005 through September 30, 2010
Project Period Covered by this Report: October 1, 2006 through September 30, 2007
RFA: Computational Toxicology: Environmental Bioinformatics Research Center (2004) RFA Text | Recipients Lists
Research Category: Computational Toxicology , Human Health , Safer Chemicals
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:
- Continued designing and implementing the framework of ebTrack, that builds upon and expands the framework of ArrayTrack through the incorporation and/or linkage of new analysis components that will be available within an integrative data management environment.
- Continued the design, implementation and evaluation of ebTrack interfaces to open source databases (e.g. PostgreSQL) and to various “external” modeling tools for facilitating wider deployment of the ebTrack/ArrayTrack system for integrative analyses of various types of “related” genomic, proteomic, and metabonomic data.
- Performed various applications of ArrayTrack for environmentally-relevant toxicants and component-by-component evaluations of ArrayTrack applications.
- Developed and applied novel, optimized statistical and pattern recognition methods (to be implemented as ebTrack components) for clustering of gene expression data.
- Updated and refined the environmental bioinformatics Knowledge Base (ebKB) in a restricted beta version for testing and internal use by ebCTC researchers; furthermore proceeded in the continuing evaluation of approaches of implementing an “open” version of ebKB (i.e. that provides alternative links to copyright-protected material).
- Continued evaluation of procedures for incorporating biochemical data into the optimization and parameter estimation of physiologically-based pharmacokinetic modeling components (modules of the MENTOR-3P system [Modeling Environment for Total Risk with Physiologically-based Pharmacokinetic modules for Populations]), focusing on Bayesian model/data “fusion” tools in conjunction with optimization techniques.
- Incorporated various “aging-related” algorithms for physiological and biochemical processes, and subsequently performed systematic sensitivity analyses of selected toxicant-specific implementations, in the physiologically-based pharmacokinetic modeling for populations framework of MENTOR-3P.
- Participated in the analysis of gene expression data associated with Dibutyl-n-Phthalates exposures (in collaboration with Project 2).
- Designed an integrative framework for “assembling and linking” DORIAN modules representing different scales of biological complexity, ranging from molecule-molecule interactions to biochemical networks to virtual organs and physiological systems.
- Initiated work on a prototype “Virtual Liver” modeling framework, evaluating alternative levels of detail in describing physical structure of the liver with respect to toxicokinetic and toxicodynamic processes with case studies focusing on TCDD.
- Developed algorithms, to be implemented as DORIAN modules, for rapid assessment of risks from chronic and multiscale exposures to mixtures of contaminants.
Future Activities:
Currently planned and ongoing activities include the following:
- Continued implementation of existing and design of new ebTrack interfaces to open source databases (e.g. PostgreSQL) and to various “external” and Center-developed modeling tools for facilitating wider-deployment and applicability of the ebTrack/ArrayTrack system for integrative analyses of various types of genomic, proteomic, and metabonomic data. This will be pursued through further incorporation of novel, optimized statistical and pattern recognition methods for clustering of gene expression data as ebTrack components, and through further analysis of ongoing applications and initiation of additional applications of ArrayTrack for environmentally-relevant toxicants (e.g., dibutyl phthalate, Arsenic, etc.) and component-by-component evaluations of ArrayTrack applications.
- Refinement of the environmental bioinformatics Knowledge Base (ebKB) and making a public beta version of ebKB available.
- Continuing development and implementation of new techniques for incorporating biochemical data into the optimization and parameter estimation components of MENTOR-3P (Modeling Environment for Total Risk with Physiologically-based Pharmacokinetic modules for Populations), focusing on Bayesian tools in conjunction with optimization techniques.
- Refinements to the framework for DORIAN (Dose-Response Information Analysis) modules representing different scales of biological complexity ranging from molecule-molecule interactions to biochemical networks to virtual organs and systems.
- Implementation of a modular “Virtual Liver” with alternative levels of detail in describing physical structure of the liver with respect to toxicokinetic and toxicodynamic processes with case studies focusing on environmentally-relevant chemicals.
- Implementation of algorithms as DORIAN modules for rapid assessment of risks from chronic and multiscale exposures to mixtures of contaminants.
- Continuing development and incorporation of diagnostic tools as DORIAN modules for sensitivity and stability analysis of mechanistic models, and demonstration with case studies focusing on environmentally-relevant chemicals.
- Experimental verification of modeling results from network models of hepatocyte metabolism, and integration of regulatory rules within metabolic network models and constraining the model such that cell capabilities in the models become more realistic.
- Metabonomic case studies focusing on (a) pathways involved in steroidogenesis pathways due to in utero exposure to phthalate esters, (b) hepatocarcinogenic potential of exposure to triazole conazoles, and (c) experimental verification of the interactions between ethanol and other central hepatic pathways and xenobiotic pathways.
- Application of SNIP (S-space Network Identification Protocol) to larger networks with higher complexity and optimal design of perturbation experiments for improved efficiency and reliability of SNIP. Additional applications to other realistic bionetworks (e.g., metabolic networks) and optimizing the performance of SNIP.
- Further application of the RS-HDMR (Random-Sampling High Dimensional Model Representation) analysis of the mechanism of action on the cooperative inhibition of aspartate transcarbamoylase, which potentially can enable deeper understanding of many biological processes that this enzyme is involved in.
- Further incorporation of cheminformatic data in Shape Signatures classification models. Ongoing case studies focus on a blood-brain barrier model.
- Continuing development of structural models for liver nuclear receptors: PXR, FXR, LXR, VDR, etc., and, molecular modeling studies of xenobiotic-NR interactions, with emphasis on chemicals from the Toxcast database and nuclear receptors found in the liver. Ongoing case studies focus on the computational structural model of FXR for Ciona (sea squirt), for comparison with x-ray structural data of FXR for other species.
- Study of new approaches, including hybrid methods, for (a) de novo protein design, (b) understanding biological coherence in gene clustering, and (c) peptide identification.
- Definition of specific case studies for comprehensive source-to-outcome modeling and analysis, and further evaluation of approaches developed at the Center through collaborative efforts with external researchers.
Journal Articles on this Report : 1 Displayed | Download in RIS Format
Other subproject views: | All 8 publications | 4 publications in selected types | All 1 journal articles |
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Other center views: | All 330 publications | 132 publications in selected types | All 118 journal articles |
Type | Citation | ||
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Georgopoulos PG. A multiscale approach for assessing the interactions of environmental and biological systems in a holistic health risk assessment framework. Water, Air, & Soil Pollution: Focus 2008;8(1):3-21. |
R832721 (2007) R832721 (2008) R832721C001 (2006) R832721C001 (2007) |
Exit Exit |
Supplemental Keywords:
Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Geographic Area, State, Risk Assessments, Biochemistry, Environmental Monitoring, Biology, Risk Assessment, ecological risk assessment, computational toxicology, toxicology, environmental risks, biopollution, outreach and training, chemical composition, New Jersey (NJ), human exposure, toxicologic assessment, bioinformatics, biochemical research, human health riskProgress and Final Reports:
Original AbstractMain 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
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
1 journal articles for this subproject
Main Center: R832721
330 publications for this center
118 journal articles for this center