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Engineering a Computable Model for Microglial-dependent Neurodevelopment
Citation:
Barham, K., R. Spencer, Nancy C. Baker, K. Carstens, AND T. Knudsen. Engineering a Computable Model for Microglial-dependent Neurodevelopment. International Neurotoxicology Association, Durham, NC, May 21 - 25, 2023. https://doi.org/10.23645/epacomptox.23271890
Impact/Purpose:
This is an invited presentation to a symposium entitled "Evaluating new approach methodologies for developmental neurotoxicity: computational models to mechanisms of toxicity", to be held at the International Neurotoxicology Association-18: Integration from high through-put screens to complex organisms to protect humans from neurotoxicity conference in Durham, NC
Description:
Microglia perform a diverse array of functions in both the development and maintenance of the nervous system, including acting as its resident macrophages. Microglial research seeks to understand their biological functions and observe how they are affected by toxicological exposure. We have begun development on a suite of computational models using the CompuCell3D modeling environment that follows microglial formation and function during neurodevelopment. This window of interest begins during gastrulation with the differentiation of epiblast cells into posterior mesoderm which gives rise to the hematopoietic blood islands, the origin site of microglial precursors, and concludes with microglial-dependent neurovascular crosstalk during blood-brain barrier morphogenesis. Models are constructed using data on cellular dynamics and communication obtained through in vivo mouse model literature where microglial dynamics have been disrupted genetically. Interfering with the genetic regulation governing our gastrulation model (E5.5-6.5) produces effects mirroring those reported in experimental mouse embryology literature, with 50% reductions in both FGF4 and BMP4 signaling resulting in 88% and 63% reductions, respectively, in the size of the posterior mesodermal population. This gives insight into the damaging effects on early hematopoietic lineages, and subsequent microglial development, posed by early chemical exposures. Our neurovascular crosstalk model (E9.5-11.5) highlights the role microglia play in promoting microvessel density in the subventricular plexus and barriergenesis, with a loss of microglia resulting in a 61% decrease in vascular density. This in silico testing platform predicts phenotypic consequences of chemical perturbation of key developmental signaling pathways based on in vitro bioactivity data to enable predictive toxicology in the animal-free zone. Disclaimer: This abstract does not necessarily reflect Agency views or policy.
URLs/Downloads:
DOI: Engineering a Computable Model for Microglial-dependent Neurodevelopment
BARHAM FINAL INA PRESENTATION.PDF (PDF, NA pp, 3832.665 KB, about PDF)