Dynamic Pattern in Chemically Reacting Systems

描述（由申请人提供）：在发育中的生物体中，适当大小，形状和空间模式的组织的生长和发育需要在模式，生长控制和细胞-细胞相互作用的信号通路输出之间取得适当的平衡。果蝇已被证明是理解控制组织发育和体内平衡的网络的理想模型系统。最近对果蝇翅盘的研究已经阐明了形成翅盘的信号通路，以及这些通路与控制细胞增殖和凋亡的Hippo信号通路相互作用的结果。我们提出的工作的总体目标是开发一个全面的、几何逼真的计算模型，用于理解实验观察到的生长和模式的时空演变，作为果蝇翅膀发育综合途径的输出。我们开发的组件模型将通过匹配野生型模式进行验证，然后用于对基因错误表达和其他干预的反应进行实验可测试的预测。我们的第一个目标是建立一个基于果蝇翅盘的细胞模型，正确地描述柱状细胞的形状，并结合信号网络。计算框架将被设计为允许所有已知的翅膀运输步骤，包括细胞素，通过与细胞外空间的受体和glyypicans结合而调节的扩散，以及胞吞作用。第二个目标是建立一个基于细胞的生长控制途径模型，该模型结合了细胞内的扩散运输和细胞间的细胞-细胞信号传导。我们的目标是确定是否所有或大部分的大量实验结果生长模式的各种过表达和低表达突变体可以解释当前定义的基因控制网络的基础上。第三个目标是建立一个综合的信号通路模型，该模型结合了前两个目标中的组成部分，并适当地结合了生长和机制。由此产生的模型将用于研究信号、生长和生长控制以及组织的机械特性如何相互作用，以在正常成人中产生适当大小的组织，什么机制解释了某些类型的突变体产生更大或更小的翅膀的适当模式，以及为什么模式与组织大小的比例在某些情况下失败。这项工作代表了首次尝试理解生长和模式的时空演变，作为在几何现实环境中控制翼发育的综合途径的输出，我们预计它将为控制圆盘中模式和生长的复杂相互作用提供重要的新见解。该模型也将被证明是实验工作的一个有价值的辅助。

DESCRIPTION (provided by applicant): The growth and development of tissues of the appropriate size, shape and spatial patterning in a developing organism requires appropriate balances between the output of signaling pathways for patterning, growth control and cell-cell interaction. Drosophila has proven to be an ideal model system for understanding the networks that control tissue development and homeostasis. Recent studies on the Drosophila wing disc have elucidated the signaling pathways used in patterning the disc, and results on the interaction of these pathways with the Hippo signaling pathway, which controls cell proliferation and apoptosis, have emerged. Our overall objective in the proposed work is to develop a comprehensive, geometrically-realistic computational model for use in understanding the experimentally-observed spatio-temporal evolution of growth and patterning as the output of the integrated pathways governing wing development in Drosophila. The component models we develop will be validated by matching wild-type patterning, and then used to make experimentally-testable predictions about the response to gene mis-expression and other interventions. Our first objective is to formulate a cell-based model of the Drosophila wing disc that correctly describes the shape of the columnar cells, and incorporates the signaling networks. The computational framework will be designed to allow for all the known transport steps in the wing, including cytonemes, diffusion modulated by binding to receptors and glypicans in the extracellular spaces, and transcytosis. The second aim is to develop a cell-based model of the growth control pathways that incorporates diffusive transport within cells and cell-cell signaling between cells. Our objective is to determine whether all or most of the numerous experimental results on growth patterns in various over- and under-expression mutants can be explained on the basis of the currently-defined gene control networks. The third aim is to develop an integrated model for the signaling pathways that incorporates the components in the first two aims and properly incorporates growth and mechanics. The resulting model will be used to investigate how signaling, growth and growth control, and mechanical properties of the tissue interact to produce the appropriate size tissue in a normal adult, what mechanisms account for the observed proper patterning of certain types of mutants that produce larger or smaller wings, and why the scaling of pattern to tissue size fails in certain circumstances. The proposed work represents the first attempt to understand the spatio-temporal evolution of growth and patterning as the output of the integrated pathways governing wing development in a geometrically-realistic environment, and we anticipate that it will provide significant new insights into the complex interactions that govern patterning and growth in the disc. The model should also prove to be a valuable adjunct to experimental work.