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v-Liver: Simulating Hepatic Tissue Lesions as Virtual Cellular Systems
SHAH, I. A., J. R. PIRONE, K. A. HOUCK, B. VALLANAT, C. CORTON, M. J. DEVITO, R. JUDSON, D. J. DIX, T. B. KNUDSEN, AND R. CONOLLY. v-Liver: Simulating Hepatic Tissue Lesions as Virtual Cellular Systems. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
The US EPA Virtual Liver (v-Liver) project is aimed at reducing the uncertainty in estimating the risk of toxic outcomes in humans by simulating the dose-dependent effects of environmental chemicals in silico. The v-Liver embodies an emerging field of research in computational tissue modeling that integrates molecular and cellular scales to simulate adverse outcomes. In the long-term the v-Liver will aid decision support through in silico experiments on new environmental chemicals to qualitatively and quantitatively explore mode-of-action (MoA) knowledge in concert with targeted in vitro studies. At its current phase of development v-Liver is a cellular systems model of a complex liver acinus: parenchymal and non-parenchymal cells represented as autonomous biological entities (“agents”) connected and spatially organized according to lobular morphology.
The tissue microenvironment is dynamically modeled with portal to centrilobular blood flow. Each agent autonomously processes inputs from the microenvironment using biological rules to generate a response. The biological rules and agent responses are derived from prior knowledge and experimental data on hepatocyte (HC) and Kupffer cell (KC) physiology. This includes a range of cellular inputs leading to HC adaptation, HC injury, KC migration, HC necrosis, apoptosis and proliferation. The v-Liver system enables in silico investigation of liver lesions as emergent tissue-level outcomes. We demonstrate the use of the v-Liver to analyze the formation of pre-neoplastic and neoplastic lesions by: (a) selecting non-genotoxic carcinogens, (b) encoding knowledge about carcinogenic MoA as biological rules, and (c) calibrating quantitative agent responses using cell-level in vitro data from ToxCast and ex vivo tissue samples.
URLs/Downloads:v-Liver: Simulating Hepatic Tissue Lesions as Virtual Cellular Systems (slide) (PDF,NA pp, 1711 KB, about PDF)
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY