DMS/NIGMS 1: Multiscale modeling of Notch signaling during long-range lateral inhibition

形态发生素的时空分布有助于组织和器官的有组织发育。 形态原分布的一种模型是主动转运，其包括基于细胞的机制，如信号传导 丝状伪足信号丝状伪足促进远处细胞之间的接触，以允许信号发生，并支持 在发育过程中的几种细胞信号模式。拟议项目将使用多尺度建模， 生物学实验以检验Notch信号传导经由丝状伪足-丝状伪足介导的细胞-细胞 体内接触。将在三个目标中检验这一假设。(1)研究Notch激活机制 在丝状伪足上不同模式的丝状伪足相互作用的力学模型将被用来量化的力量 在丝状伪足介导的信号传导过程中产生，以确定Notch激活的最可能机制。（二） 确定Notch信号如何传递到细胞体。存在下丝状伪足的数学模型 将研究信号的扩散和主动传输，以量化每种机制的相对重要性。 我们将支持我们的模型与遗传方法和定量活成像。(3)创建多比例顶点 Notch信号在刚毛细胞图案化过程中的模型。我们将联合收割机结合上述分子和细胞亚单位Notch信号模型，以创建图案化胸部的真正多尺度顶点模型。这一框架将 支持通过发信号的丝状伪足对图案化动力学的计算机实时研究，以识别潜在的 这个过程的分子调节器。该提案的成功将导致对 在组织形成过程中驱动长距离侧抑制的机制。我们将介绍第一个多尺度 苍蝇胸部的机械模型，允许丝状伪足的细胞驱动动力学和 缺口。这里提出的实验工作解决了我们对组织发育的理解中的一个主要空白 稳态：活跃的细胞过程如何促进信号的分布和激活。

The spatiotemporal distribution of morphogens contributes to the organized development of tissues and organs. One model of morphogen distribution is active transport, which includes cell based mechanisms like signaling filopodia. Signaling filopodia facilitate contact between distant cells in order to allow signaling to occur, and support several cell signaling paradigms during development. The proposed project will use multi-scale modeling and biological experiments to test the hypothesis that Notch signaling occurs via filopodia-filopodia mediated cell-cell contacts in vivo. This hypothesis will be tested in three objectives. (1) Investigate the mechanism of Notch activation on filopodia. A mechanical model of distinct modes of filopodia interactions will be used to quantify the forces generated during filopodia mediated signaling to identify the most likely mechanism for Notch activation. (2) Determine how Notch signal is relayed to the cell body. A mathematical model of filopodia in the presence of diffusion and active transport of signals will be developed to quantify the relative importance of each mechanism. We will support our model with genetic approaches and quantitative live imaging. (3) Create a multi-scale vertex model of Notch signaling during bristle cell patterning. We will combine the above molecular and cellular submodels of Notch signaling to create a truly multi-scale vertex model of the patterning thorax. This framework will support an in silico, real-time investigation of patterning dynamics via signaling filopodia to identify potential molecular regulators of this process. The success of this proposal will result in a foundational understanding of the mechanisms that drive long-range lateral inhibition during tissue patterning. We will introduce the first multi-scale mechanical model of the fly thorax that allows for cell-driven dynamics of filopodia and real-time activation of Notch. The experimental work proposed here addresses a major gap in our understanding of tissue development and homeostasis: how active cell processes contribute to the distribution and activation of signals.