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2007 Progress Report: Environmental Bioinformatics and Computational Toxicology Center
EPA Grant Number: R832721Center: New Jersey Research Center for Environmental Bioinformatics and Computational Toxicology
Center Director: Welsh, William J.
Title: Environmental Bioinformatics and Computational Toxicology Center
Investigators: Welsh, William J. , Androulakis, Ioannis , Floudas, Christodoulos , Georgopoulos, Panos G. , Ierapetritou, Marianthi , Rabitz, Herschel , Tong, Weida
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, 2006 through September 30, 2007
Project Amount: $5,422,135
RFA: Computational Toxicology: Environmental Bioinformatics Research Center (2004)
Research Category: Health Effects , Computational Toxicology
Description:
Objective:ebCTC brings together a team of computational scientists, with diverse backgrounds in bioinformatics, cheminformatics and enviroinformatics, from UMDNJ, Rutgers, and Princeton Universities, and the USFDA’s Center for Toxicoinformatics. This team is addressing, in a systematic and integrative manner, multiple elements of the toxicant Source-to-Outcome sequence as well as developing cheminformatics tools for toxicant characterization. The computational tools being developed through this effort are extensively evaluated and refined through collaborative applications involving ebCTC scientists as well as colleagues from the three universities, USFDA and USEPA; particular emphasis is on methods that enhance current quantitative risk assessment practices and reduce uncertainties.
Progress Summary:During the second year of Center activities, (a) specific steps were taken towards integrating developmental efforts from the various ongoing research projects of the Center, and (b) new collaborations were established involving scientists from other institutions and EPA, to enhance research in critical areas. A representative sample of specific accomplishments includes:
Data Analysis Methods and Computational Tools
- Progress in expanding the framework of ArrayTrack to ebTrack and in the development of new analysis components for incorporation into ebTrack. Evaluation and design of interfaces to open source databases (e.g. PostgreSQL) and to various “external” modeling tools for enabling wider-deployment of the ebTrack/ArrayTrack system for integrative analyses of various types of genomic, proteomic, and metabonomic data. Development of computational tools for peptide identification from tandem mass spectrometry data and novel, optimized statistical and pattern recognition methods for clustering of gene expression data (these tools are to be implemented as ebTrack components).
- Application of novel techniques for analysis of time-series gene expression data and identification of informative genes to support risk analysis tasks: Application to exposures to phthalates with identification of critical gene expression motifs, associated gene ontology functions, maximally affected pathways and subsequent cross-species extrapolation conservation of protein sequences between rat and human.
Diagnostic Analysis Methods and Computational Tools
- Enhancements to the Random-Sampling High Dimensional Model Representation (RS-HDMR) algorithm for sensitivity and uncertainty analysis: Application to (a) toxicokinetic modeling of Arsenic and of aromatic hydrocarbon mixtures; (b) allosteric regulation of aspartate transcarbamoylase (AtCase) by all four ribonucleotide triphosphates (NTPs).
- Optimization and refinement of sensitivity analysis techniques for usage with PBPK modeling: Application to novel models for aging organisms and populations.
- Development and evaluation of a Bayesian computational framework for exposure reconstruction from biomarker data using toxicokinetic models and numerical inversion methods: Applications to the NHEXAS and NHANES datasets.
Molecular Modeling Methods and Computational Tools
- Ongoing development of computational tools for de novo protein design and high resolution protein structure determination: Applications to prediction of interhelical restraints for alpha helical proteins.
- Ongoing development, enhancement and application of the Shape Signatures QSAR technology for chemical hazard identification: (a) Demonstrations with applications involving conazoles, (b) Development of a Shape Signatures database of ligands extracted from the Protein Data Bank (PDB), and (c) Application of a multi-step screening procedure using Shape Signatures and clustering to identify previously unrecognized antiestrogenic chemicals.
- Molecular modeling studies of ligand-PXR interactions: Applications to binding of conazoles, azoles, steroids and various other structural families to the AF-2 site.
Bionetwork Modeling Methods and Tools
- Development of customized metabolic engineering tools for identifying important pathways within the overall hepatocyte metabolism.
- Development and demonstration of novel computational procedures for quantifying the structure of molecular bionetworks via the S-space Network Identification Protocol (SNIP).
Integrative Toxicokinetic/Toxicodynamic Modeling for Biologically-Based Dose-Response Analysis
- Development of algorithms for rapid assessment of risks from chronic and multiscale exposures to mixtures of contaminants: Applications to halogenated organics.
- Progress in designing/implementing and demonstrating the modular multiscale DORIAN (Dose-Response Information Analysis) framework to support mechanistic toxicity and - in conjunction with the Modeling Environment for Total Risk (MENTOR) - comprehensive risk assessment studies: Selected preliminary applications use Arsenic as a “prototype” toxicant.
Special Note: New Collaborations
A major effort during this reporting period involved reaching out to other scientists, with research interests relevant to the scope of ebCTC, in order to establish collaborations in critical research areas. Indeed, during the 2006-2007 period, new collaborations were established with:
- Dr. Sean Ekins of the University of Maryland School of Pharmacy (Projects 4 and 1)
- Dr. Charles Roth of the Department of Biomedical Engineering of Rutgers University (Projects 1 and 2)
- Dr. Kannan Krishnan of the University of Montreal Department of Occupational and Environmental Health (Project 1)
- Dr. Sridhar Mani of the Albert Einstein Cancer Center Department of Pharmacology (Project 4)
- Dr. Matthew Krasowski of the University of Pittsburgh School of Medicine (Project 4)
- Dr. Joshua Rabinowitz of Princeton University Department of Chemistry (Project 3)
- Drs. Calvin Walker, Jose Serrano, Michael Hemmer and Kimberly Salinas of USEPA (Project 5).
In addition to the newly initiated collaborations listed above, ongoing collaborations continue with:
- Drs. Mike Devito, Marina Evans, Elaina Kenyon and Mike Tornero of USEPA NHERL on the impact of aging on population toxicokinetics (MENTOR-DORIAN components; Project 1)
- Dr. Amit Roy of Bristol Myers Squibb on techniques for reconstruction of exposures from biomarkers (MENTOR-DORIAN components; Project 1)
- Dr. Susan Hester of USEPA NHEERL (Project 2)
- Drs. Susan Euling and Banalata Sen of USEPA NCEA (Projects 1 and 2)
- Drs. Donald Gerecke, Jeff Laskin, and Yoke-Chen Chang of EOHSI on case studies with ebTrack/ArrayTrack (Project 1)
- Dr. Kevin Gaido of CIIT-Hamner Institute (Project 2)
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: 20 Displayed | Download in RIS Format
| Other center views: | All 103 publications | 24 publications in selected types | All 20 journal articles |
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Androulakis IP, Yang E, Almon RR. Analysis of time-series gene expression data: methods, challenges, and opportunities. Annual Review of Biomedical Engineering 2007;9:205-228. |
R832721 (2007) |
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Davis E, Ierapetritou M. A kriging method for the solution of nonlinear programs with black-box functions. AIChE Journal 2007;53(8):2001-2012. |
R832721 (2007) |
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DiMaggio Jr PA, Floudas CA. A mixed-integer optimization framework for de novo peptide identification. AIChE Journal 2007;53(1):160-173. |
R832721 (2007) R832721C005 (2006) |
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DiMaggio Jr PA, Floudas CA. De novo peptide identification via tandem mass spectrometry and integer linear optimization. Analytical Chemistry 2007;79(4):1433-1446. |
R832721 (2007) |
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Ekins S, Chang C, Mani S, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, Swaan PW, Patel R, Bachmann K. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Molecular Pharmacology 2007;72(3):592-603. |
R832721 (2007) |
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Floudas CA. Computational methods in protein structure prediction. Biotechnology and Bioengineering 2007;97(2):207-213. |
R832721 (2007) |
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Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. An indirect response model of endotoxin-induced systemic inflammation. Journal of Critical Care 2007;22(4):337-338. |
R832721 (2007) |
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Fung HK, Welsh WJ, Floudas CA. Computational de novo peptide and protein design: rigid templates versus flexible templates. Industrial & Engineering Chemistry Research 2008;47(4):993-1001. |
R832721 (2007) |
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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):1567-7230. |
R832721 (2007) |
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Jiao Y, Su M, Chen M, Jia W, Chou Y, Huang Z, Yang N, Tong W. LC/ESI-MS method for the determination of trimetazidine in human plasma: application to a bioequivalence study on Chinese volunteers. Journal of Pharmaceutical and Biomedical Analysis 2007;43(5):1804-1807. |
R832721 (2007) |
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Jornsten R, Ouyang M, Wang H-Y. A meta-data based method for DNA microarray imputation. BMC Bioinformatics 2007;8:109. |
R832721 (2007) |
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McAllister SR, Mickus BE, Klepeis JL, Floudas CA. Novel approach for α-helical topology prediction in globular proteins: generation of interhelical restraints. Proteins: Structure, Function, and Bioinformatics 2006;65(4):930-952. |
R832721 (2007) |
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Rajgaria R, McAllister SR, Floudas CA. A novel high resolution Cα—Cα distance dependent force field based on a high quality decoy set. Proteins: Structure, Function, and Bioinformatics 2006;65(3):726-741. |
R832721 (2007) R832721C005 (2006) |
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Wang CY, Ai N, Arora S, Erenrich E, Nagarajan K, Zauhar R, Young D, Welsh WJ. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach. Chemical Research in Toxicology 2006;19(12):1595-1601. |
R832721C004 (2006) |
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Yang E, Foteinou PT, King KR, Yarmush ML, Androulakis IP. A novel non-overlapping bi-clustering algorithm for network generation using living cell array data. Bioinformatics 2007;23(17):2306-2313. |
R832721 (2007) |
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Yang E, Maguire T, Yarmush ML, Berthiaume F, Androulakis IP. Bioinformatics analysis of the early inflammatory response in a rat thermal injury model. BMC Bioinformatics 2007;8:10. |
R832721 (2007) |
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Yang E, Simcha D, Almon RR, Dubois DC, Jusko WJ, Androulakis IP. Context specific transcription factor prediction. Annals of Biomedical Engineering 2007;35(6):1053-1067. |
R832721 (2007) |
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Yang E, Almon RR, DuBois DC, Jusko WJ, Androulakis IP. Extracting global system dynamics of corticosteroid genomic effects in rat liver. Journal of Pharmacology and Experimental Therapeutics 2008;324(3):1243-1254. |
R832721 (2007) |
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Yang E, Maguire TJ, Yarmush ML, Berthiaume F, Androulakis IP. Identification of regulatory mechanisms of the hepatic response to thermal injury. Computers & Chemical Engineering 2008;32(1-2):356-369. |
R832721 (2007) |
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Yang E, Maguire T, Yarmush ML, Androulakis IP. Informative gene selection and design of regulatory networks using integer optimization. Computers & Chemical Engineering 2008;32(4-5):633-649. |
R832721 (2007) |
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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, dose-response, toxicology, environmental risks, risk, outreach and training, computational toxicology, New Jersey (NJ)
Relevant Websites:
Progress and Final Reports:
2006 Progress Report
Original Abstract
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