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v-Liver: Simulating Hepatic Tissue Lesions as Virtual Cellular Systems
Citation:
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.
Impact/Purpose:
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.
Description:
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.