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

形态物质的时空分布有助于组织器官的有组织发育。 形态分布的一种模式是主动转运，它包括基于细胞的机制，如信号传递 丝状伪足。信号丝状孔促进了远距离细胞之间的联系，以便允许信号的发生，并支持 发育过程中的几种细胞信号模式。拟议的项目将使用多尺度建模和 验证Notch信号通过丝状伪足-丝状伪足介导的细胞-细胞的假说的生物学实验 活体内有接触。这一假设将在三个目标中得到检验。(1)探讨缺口激活的机制 在丝状伪足上。我们将使用不同的丝状足相互作用模式的机械模型来量化作用力。 在丝状孢子介导的信号传递过程中产生，以确定Notch激活的最可能机制。(2) 确定Notch信号如何传递到细胞体。存在丝状伪足的数学模型 将发展信号的扩散和主动传输，以量化每种机制的相对重要性。 我们将用遗传方法和定量活体成像来支持我们的模型。(3)创建多比例顶点 刚毛细胞构图过程中的Notch信号模型。我们将结合上述Notch信号的分子和细胞子模型来创建一个真正多尺度的胸腔图案顶点模型。这一框架将 通过发送丝状基座信号来识别潜在的图形动态，从而支持对图形动态的计算机实时研究 这一过程的分子调节器。这项提议的成功将导致对 在组织构图过程中驱动远程侧向抑制的机制。我们将介绍第一个多尺度 苍蝇胸腔的机械模型，允许细胞驱动的丝状足细胞动力学和实时激活 开槽。这里提出的实验工作解决了我们对组织发育理解上的一个主要差距。 动态平衡：活跃的细胞过程如何对信号的分布和激活做出贡献。

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.