Grantee Research Project Results
Final Report: Ontologies for Data & Models for Liver Toxicology
EPA Grant Number: R835001Title: Ontologies for Data & Models for Liver Toxicology
Investigators: Glazier, James A
Institution: Indiana University - Bloomington
EPA Project Officer: Chung, Serena
Project Period: June 1, 2011 through May 30, 2015
Project Amount: $749,705
RFA: Computational Toxicology: Biologically-Based Multi-Scale Modeling (2010) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability
Objective:
The EPA-funded Liver consortium consists of four Institutions that extend existing EPA research in predicting human liver toxicity of environmental toxins.
This document outlines progress that the Biocomplexity Group (BlOC) at Indiana University, along with our subcontractor Prof. Tony Hunt of UCSF, has made on the aims of our proposal during the three years of the project.
Summary/Accomplishments (Outputs/Outcomes):
Aim 1: Develop an extensible multi-scale liver behavior Ontology.
The Cell Behavior Ontology (CBO) manuscript was published in March 2014. That manuscript gives a detailed use-case describing the annotation of multi cell models using OWL CBO (along with other bio-ontologies) in which the entities (cells, extracellular matrix (ECM), vasculature), process (cell growth, death...) and spatial evolution of the entities over time is described. The CBO fills an important gap in existing bio-ontologies in that it allows the definition of spatial characteristics of cells, tissues and organs. The CBO has been deposited in the BioPortal database at Cell Behavior Ontology Exit.
In addition to the CBO, we have converted a published ontology on Drug Induced Liver Injury (DJLio) into an OWL ontology and deposited that ontology in the BioPortal database at Drug-Induce Liver Injury (combined) Exit
Aim 2: Develop a set of extensible Application Programming Interfaces (APls) and data-encapsulation standards, including interchange-language, intermediate-language and executable language specifications.
We have refined the API to Compucell3D and in collaboration with Dr. Hunt's group at UCSF carried out a proof of concept study in which Compucell3D is called, via its API, by Dr. Hunt's MASON simulation system. In addition, in collaboration with Prof. Herbert Sauro at Univ. Washington we have completely rewritten the SBML API, now called LibRoadRunner, and included that SBML solver package in the Compucell3D distribution. The SBML model (both subcellular reaction kinetic and whole-body SBML) portions of our multiscale liver simulation use this new SBML execution library.
Aim 3: Create a Graphical User Interface (GUI) tool, the Virtual Liver Builder, to build, document, view and maintain model and experiment data.
Progress in this aim includes enhancements to the Compucell3D user interface and the creation of CellDraw, a graphical tool for the development of spatial models suitable for use as initial conditions for Compucell3D (CC3D) simulations. Cell Draw is a graphical tool with which users can draw and fill regions of computational space with cells of specified types as a starting configuration for in silico CC3D models. Cell Draw also can import microscope images for manual segmentation and conversion into starting configurations for models. Two recent additions to Cell Draw are "Scene Bundles" and the direct import of 3D segmentation files.
CC3D Scene Bundles are used to describe behavioral and data concepts for simulated environments. The top file points to a directory with a standardized hierarchical structure that holds separate files for spatial region properties, cell type properties, and cell lattice properties.
In addition, we have created annotated physiologically based pharmacokinetic (PBPK) and subcellular reaction kinetic models of acetaminophen that will be deposited in the BioModels database when the manuscript describing our multi-scale acetaminophen model is published. These models are executable on their own (within their spatial domain) and can be easily incorporated into the modeling efforts of outer groups.
Our most significant progress in this area was the creation of multi-scale models of liver toxicity by both the JU and UCSF groups. These models include whole body PBPK models, liver tissue models (in both two and three dimensions) and subcellular reaction kinetic models of acetaminophen metabolism and toxicity. These models have been published or are manuscripts in preparation. In addition, the UCSF group has developed models of in vitro cell cultures of hepatocytes.
A flow model of a simulated liver lobule model was also created. Using this model, blood flow and oxygen distribution in the 3D simulated model was calculated.
Aim 4: Create sharable repository structures for cell types, tissue components (e.g. vasculature and lobules) and virtual livers useable as starting templates for the Virtual Liver Builder.
Besides the multiscale models described under Aim 3, work related to this aim includes a collaboration with Dr. John Wambaugh of the EPA, Prof. Alex Tropsha (UNC) and others on incorporating QSAR based predictions into multiscale toxicity models. This work was presented as a poster (see publications Appendix) and a manuscript is in preparation.
In addition to the model modules listed above we have created annotated SBML models for acetaminophen metabolism as well as a PBPK model for acetaminophen adsorption, distribution and excretion. We annotated these models to the BioModels Exit (http://www.ebi.ac.uk/biomodelsmain/) level of "curated" models and they will be deposited in the BioModels database when the manuscript is submitted.
Aim 5: Document, open-source release and support the ISLF tools in Aims 1-4 in a Semantic Web compatible format.
Work relating to this aim includes the publication of the cell Behavior Ontology and the conversion of an ontology of Drug Induced Liver Injury, created by other workers, and deposition of both ontologies in the BioPortal repository.
Ontologies:
The Cell Behavior Ontology (CBO) deposited in BioPortal http://bioportal.bioontology.org/ontologies/CBO Exit.
Drug Induced Liver Injury Ontology (DILlo) deposited in BioPortal http://bioportal.bioontology.org/ontologies/DILIo
Journal Articles on this Report : 6 Displayed | Download in RIS Format
| Other project views: | All 24 publications | 7 publications in selected types | All 6 journal articles |
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Andasari V, Roper RT, Swat MH, Chaplain MAJ. Integrating intracellular dynamics using CompuCell3D and BioNetSolver: applications to multiscale modelling of cancer cell growth and invasion. PLoS ONE 2012;7(3):e33726. |
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Petersen BK, Ropella G, Hunt CA. Toward modular biological models: defining analog modules based on referent physiological mechanisms. BMC Systems Biology 2014;8:95. |
R835001 (Final) |
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Sluka JP, Glazier JA, Swat M. Infrastructure requirements for moving multiscale modeling from research tools to the clinical and regulatory domains. VPH NoE Newsletter 2012;7:12. |
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Sluka J, Shirinifard A, Swat M, Cosmanescu A, Heiland RW, Glazier J. The Cell Behavior Ontology: describing the intrinsic biological behaviors of real and model cells seen as active agents. Bioinformatics 2014;30(16):2367-2374. |
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Wambaugh JF, Wetmore BA, Pearce R, Strope C, Goldsmith R, Sluka JP, Sedykh A, Tropsha A, Bosgra S, Shah I, Judson R, Thomas RS, Setzer RW. Toxicokinetic triage for environmental chemicals. Toxicological Sciences 2015;147(1):55-67. |
R835001 (Final) R835166 (2015) R835166 (2016) R835166 (Final) |
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Wang Y, Lin Z, Liu Z, Harris S, Kelly R, Zhang J, Ge W, Chen M, Borlak J, Tong W. A unifying ontology to integrate histological and clinical observations for drug-induced liver injury. American Journal of Pathology 2013;182(4):1180-1187. |
R835001 (Final) |
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Supplemental Keywords:
Human liver, liver toxicity, environmental toxins, virtual liver, GUI tool, graphical user interface tool;Progress and Final Reports:
Original AbstractThe 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.