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Computer Simulation of Embryonic Systems: What can a virtual embryo teach us about developmental toxicity? Microcephaly: Computational and organotypic modeling of a complex human birth defect (seminar and lecture - Thomas Jefferson University, Philadelphia, PA)
Citation:
Knudsen, T. Computer Simulation of Embryonic Systems: What can a virtual embryo teach us about developmental toxicity? Microcephaly: Computational and organotypic modeling of a complex human birth defect (seminar and lecture - Thomas Jefferson University, Philadelphia, PA). Presented at TJU Seminar & Lecture, Philadelphia, PA, May 24 - 25, 2016. https://doi.org/10.23645/epacomptox.5077687
Impact/Purpose:
(1) "Computer Simulation of Embryonic Systems: What can a virtual embryo teach us about developmental toxicity?" is an invited seminar at the Thomas Jefferson University Alumni Seminar Series. (2) "Microcephaly: Computational and organotypic modeling of a complex human birth defect" is an invited lecture in the graduate course on teratology.
Description:
(1) Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research program (ToxCast) generated vast in vitro cellular and molecular effects data on >1858 chemicals in >600 high-throughput screening (HTS) assays. The diversity of assays has been increased for developmental toxicity with several HTS platforms, including the devTOX-quickPredict assay from Stemina Biomarker Discovery utilizing the human embryonic stem cell line (H9). Translating these HTS data into higher order-predictions of developmental toxicity is a significant challenge. Here, we address the application of computational systems models that recapitulate the kinematics of dynamical cell signaling networks (e.g., SHH, FGF, BMP, retinoids) in a CompuCell3D.org modeling environment. Examples include angiogenesis (angiodysplasia) and dysmorphogenesis. Being numerically responsive to perturbation, these models are amenable to data integration for systems Toxicology and Adverse Outcome Pathways (AOPs). The AOP simulation outputs predict potential phenotypes based on the in vitro HTS data ToxCast. A heuristic computational intelligence framework that recapitulates the kinematics of dynamical cell signaling networks in the embryo, together with the in vitro profiling data, produce quantitative predictions of dose-response and gestational susceptibilities. (2) Zika virus and the?recent outbreak of microcephaly has raised significant health concerns for pregnancy. As part of our mission to protect human health and safeguard the environment, EPA is working with our federal partners and other stakeholders to combat the recent outbreak of the Zika virus. Because the Zika virus is vectored by mosquitoes (Aedes aegypti and Aedes albopictus), EPA’s role is to encourage responsible and effective mosquito control, including Integrated Pest Management (IPM), and individual protection from mosquito bites. This includes education and outreach. Microcephaly may be the ‘tip of the’ iceberg and many conditions are known to precipitate this adverse outcome during early pregnancy. As such, the need arises for computational and experimental models that can be used to probe and validate the many possible explanations and connections. Case use for an Adverse Outcome Pathway (AOP) framework of ‘microcephaly’ that scales to ToxCast/Tox21 libraries for predictive toxicology.
URLs/Downloads:
DOI: Computer Simulation of Embryonic Systems: What can a virtual embryo teach us about developmental toxicity? Microcephaly: Computational and organotypic modeling of a complex human birth defect (seminar and lecture - Thomas Jefferson University, Philadelphia, PA)
KNUDSEN_TJU_COMPBIO_2016_SEMINAR.PDF (PDF, NA pp, 5448.25 KB, about PDF)
KNUDSEN_MAY_24_MCPH_TJU_LECTURE.PDF (PDF, NA pp, 2843.815 KB, about PDF)