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Quantitative prediction of microcephaly utilizing cell agent-based modeling: profiling the centrosome cycle (Teratology Society Annual Meeting)
Citation:
Zurlinden, T., K. Saili, R. Spencer, N. Baker, AND T. Knudsen. Quantitative prediction of microcephaly utilizing cell agent-based modeling: profiling the centrosome cycle (Teratology Society Annual Meeting). Presented at Teratology Society Annual Meeting, Denver, Colorado, June 24 - 28, 2017.
Impact/Purpose:
Abstract for presentation at the Teratology Society annual meeting on a computational model of the neurovascular unit (cNVU) that incorporates extant knowledge of human embryology and recapitulates the spatiotemporal dynamics of the centrosome cycle during early brain development will provide a useful tool to address key events in an adverse outcome pathway (AOP) for microcephaly.
Description:
Microcephaly is a human birth defect that is precipitated by diverse genetic and environmental factors including recessive mutations in the centrosome cycle, prenatal exposure to alcohol or methylmercury, and maternal Rubella or Zika viral infections. A computational model of the neurovascular unit (cNVU) that incorporates extant knowledge of human embryology and recapitulates the spatiotemporal dynamics of the centrosome cycle during early brain development will provide a useful tool to address key events in an adverse outcome pathway (AOP) for microcephaly. Query of the Mammalian Phenotype Browser database for ‘microcephaly’ (MP:0000433) returned 12 gene associations that function in microtubule assembly and centrosome cycle linked to microcephalin (MCPH1), the human gene for primary microcephaly. This pathway is critical in the developing ventricular zone of the rudimentary brain, where neuroprogenitor cells (NPCs) self-replicate during the 1st trimester patterning brain size and neural differentiation. Chemical or viral disruption of the logistical dynamics of NPC growth and differentiation is posited as a subsequent key event. To model these dynamics, a cell agent-based model was developed to address the interactions of multiple cell types in the NVU (endothelial cells, microglia, neural cells) at various states of morphogenesis and differentiation. In addition to the cell-cycle checkpoint (MCPH1), the state map driving the simulation included the checkpoint pathways in the cell cycle governing centriole assembly (CASC5, CEP152, WDR62) and orientation (ASPM). Simulation results determine probabilistic outcomes indicative of neurogenic precursor populations that determine brain size and that can be linked to extant mathematical models of cellular dynamics. The cNVU model can be used to translate in vitro data on NPC cellular dynamics (e.g., drug, chemical, viral) into a probabilistic prediction of key events leading to microcephaly. [This abstract may not reflect US EPA policy].