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ASCB 2007 American Society for Cell Biology
Poster: Sunday, December 2, 2007, program 219, board B153
Presented 12:00n-1:30p by Mason Vail.
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Computational Models of Epithelial Morphogenesis

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Accompanying handout

Abstract
To analyze processes that produce, maintain or disrupt epithelial organization and function, we have devised “middle-out” in silico models where molecules, genes, gene regulatory networks, metabolic pathways and physical parameters are represented in a cell-based computational architecture that grows 3D virtual epithelia. The platform includes primitives for gene expression, signaling, adhesion, extracellular matrix, transport and surface binding, molecule turnover, growth, division, and apoptosis. Higher order properties are not specified, but instead emerge from transactions carried out within and between cells according to the physics of the model. A user can monitor or manipulate the internal state of any cell, introduce targeted mutations or gene knock-outs, and monitor the effects on subsequent growth, differentiation and organization. A self-repairing virtual epidermis developed on this platform is responsive to injury or mutation: it exhibits dynamic turnover through death and sloughing of cells at the apical surface coupled with replenishment from basal cells. Mutations that promote aberrant cell division produce aggressive, locally invasive clumps of small, neoplastic virtual cells with diminished keratin, similar to basal cell carcinoma. To understand the role of stem cells in epithelial renewal, using the same platform we devised self-organizing models of stem niches based on the Drosophila “hub-rosette” niche with asymmetric division and JAK-STAT signaling for maintaining stem cell identity. In a fully-formed niche, a cluster of ~12 hub cells attached to basement membrane is surrounded by 5-6 germ-line stem cells that give rise to transit amplifying cells destined eventually to become spermatocytes. These studies indicate that in silico models can help to predict effects of mutations or physical manipulations on epithelial organization and function, in vivo or in culture, or they can serve as high-throughput hypothesis testers for refinement of wet-bench studies.


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