Mathematical Modeling of Robust Spatiotemporal Dynamics in Epidermal Development

University Of Nebraska-Lincoln, Lincoln NE

Investigators

Abstract

The project will develop a new generation of multiscale and stochastic models capable of integrating experimental data to study mouse epidermal development that includes chemical regulation and mechanical aspects of the system in a mechanistic, data-informed manner. Epidermal morphogenesis, which occurs during the second half of embryogenesis, is the developmental process that generates a skin permeability barrier essential for terrestrial survival. Defects with this barrier are associated with common skin disorders such as atopic dermatitis. Study of mechanisms that control epidermal development and differentiation is therefore highly relevant to human health. Comprehensive knowledge about adult epidermal homeostasis and regeneration, as well as adult epidermal stem cell biology, has been accumulated for decades. However, embryonic development of the epidermis, especially in the early period, still needs exploration. The overall goal of this project is to help address this knowledge gap by developing mathematical results and tools to unravel critical mechanisms underlying epidermal development that are generally applicable to multiple organisms and differentiation/developmental processes. The project will involve close multi-disciplinary interactions among students and researchers in the fields of biology, mathematics, statistics, and engineering cross colleges and universities in Nebraska with a commitment to enhancing the recruitment and support of female and underrepresented minority students. The project will investigate mechanical, chemical, and gene regulatory processes in a comprehensive modeling platform to understand how these processes influence epidermal development and its defects that may lead to an improved understanding of skin and other epithelial systems such as the tongue, esophagus, stomach, and the olfactory epithelium. Interactions among three major biological scales will be investigated: transcription factors within a cell, individual cells of different fates (or different intracellular states), and the epidermis consisting of many cells and diffusive regulatory molecules secreted from the cells. In order to do this, the project will first develop a 3D spatial multiscale model based on a novel anisotropic subcellular element method to account for structural aspects of the epidermis for self-organization. The project will then use a hybrid model consisting of a non-spatial cell lineage model with several cell stages and the spatial model to investigate the coupling of the biochemical and dynamical mechanisms of the organization with stochasticity that accounts for stochastic gene regulation and the interplay between gene regulation and extracellular signaling profile of the epidermis. Existing data where available will be used to inform model development, and the results will identify experiments capable of probing the mechanism responsible for robust epidermal organization. The project will also develop a new unified computational toolkit for modeling and simulating the interplay between discrete cells, biochemical signaling, gene regulation, and continuum mechanics that will have broad applications. This project is jointly funded by the Math Biology Program of the Division of Mathematical Sciences (DMS) and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.