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

DMS/NIGMS 1：长程侧向抑制期间 Notch 信号传导的多尺度建模

• 批准号: 10797357
• 负责人: Emmanuel Asante-Asamani
• 金额: $ 19.8万
• 依托单位: CLARKSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797357
• 关键词: Active Biological Transport; Address; Biological; Cell physiology; Cells; Chest; Defect; Development; Diffusion; Disease; Distant; Event; Filopodia; Homeostasis; Human; Image; Investigation; Lateral; Mechanics; Mediating; Modeling; Molecular; Multiscale Mechanics; National Institute of General Medical Sciences; Organ; Pattern; Process; Receptor Signaling; Signal Transduction; Signaling Molecule; Testing; Time; Tissues; Work; experimental study; fly; genetic approach; in silico; in vivo; mathematical model; morphogens; multi-scale modeling; notch protein; spatiotemporal; success

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.

形态剂的时空分布有助于组织和器官的有组织发展。 形态学分布的一种模型是主动传输，其中包括基于细胞的机制，例如信号传导 丝状。信号传导丝虫促进远处细胞之间的接触以允许发出信号并支撑 发育过程中的几个细胞信号传导范例。拟议的项目将使用多尺度建模和 生物学实验测试了通过丝状丝虫介导的细胞 - 细胞细胞介导的Notch信号传导的假设 接触体内。该假设将以三个目标进行检验。 （1）研究Notch激活的机制 在丝状上。不同的丝状相互作用模式的机械模型将用于量化力 在丝状介导的信号传导过程中生成，以识别最可能的凹槽激活机制。 （2） 确定Notch信号如何中继到细胞体。在存在的情况下的数学模型 将开发信号的扩散和主动传输，以量化每种机制的相对重要性。 我们将通过遗传方法和定量实时成像来支持我们的模型。 （3）创建一个多尺度顶点 刷毛细胞模式期间的Notch信号传导模型。我们将结合上述Notch信号传导的分子和细胞子模型，以创建一个真正的多尺度顶点模型。这个框架将 支持在硅中，通过信号传导丝状对模式动态进行实时研究，以识别潜力 该过程的分子调节剂。该提案的成功将导致对 在组织模式期间驱动长距离横向抑制的机制。我们将介绍第一个多尺度 蝇胸的机械模型，允许通过细胞驱动的丝状动力学和实时激活 缺口。这里提出的实验工作解决了我们对组织发育的理解的主要差距 和稳态：主动细胞过程如何促进信号的分布和激活。