Hybrid mathematical modeling for cell fate determination in clustered cell migration

细胞的命运，可以说是生命最基本的组成部分，受到许多因素的指导，其中包括内部驱动和外部影响。 随着细胞在群体中的生长，差异出现，角色建立。 不同的角色是如何建立的？ 什么样的影响力在决策中是最重要的？ 在时间和空间上，产生增长模式的角色和影响的相互作用是什么？ 数学试图发现模式，并将数学建模应用于注定要迁移和集群旅行的细胞，将描述内在和外在信号之间的平衡。在那些难以在实验中可视化并随时间变化的领域，理论和计算可以指导发现决定细胞命运和决策的工作原理，最终促进正常发育并阻止恶性生长。 这项研究还将培养不同的研究人员，以履行他们在科学发现中的作用。成功的细胞迁移对于人类发育、免疫反应和某些疾病的进展至关重要，但仍有许多未知之处。特别是，我们对细胞如何随着时间的推移在体内通过复杂组织环境的知识存在许多空白。该项目将利用数学建模和简单、遗传上易于处理的果蝇卵巢来解决有关细胞如何获得运动性、与邻近细胞协调行为以及在器官内移动的悬而未决的问题。 在许多情况下，细胞之间关于这些行为的通信必须通过细胞外空间发生。目前还不清楚细胞外信号分子，如化学引诱剂和细胞因子，是如何分布在组织中，以及如何空间依赖性的浓度差异可能会影响信号。例如，细胞外信号，如未配对（UPD），可以与跨膜Janus激酶（JAK）相互作用以激活负责细胞命运运动决定的信号转导和转录激活因子（STAT）。该假设是异形胞外域影响信号分布和运动细胞行为，这可以通过基于混合剂的模型与细胞外信号转化为细胞内信号传导和运动的反应扩散模型相结合来揭示。 基于成像数据，我们将准确地模拟组织结构的异质性，并研究这种物理约束对分子扩散和信号传导的影响。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Fate of the cell, arguably the most basic building block of life, is guided by many things, internal drive and external influences among them. As cells grow in community, differences arise and roles are established. How are different roles established? What influences are paramount in deciding? What is the interplay of roles and influences that produces the growing pattern, in time and space? Mathematics seeks to discover patterns and applying mathematical modeling to cells that are fated to migrate and travel in clusters will describe the balance between intrinsic and extrinsic signals. In domains that are challenging to visualize in experiments and that change over time, theory and computation can guide discovery of the principles at work determining cell fate and decision-making, ultimately to facilitate normal development and to hinder malignant growth. This research will also train diverse researchers to fulfill their roles in scientific discovery. Successful cell migration is critical for human development, immune response, and advancement of some diseases, but much remains unknown. In particular, there are many gaps in our knowledge of how cells navigate in vivo through complex tissue environments over time. This project will leverage mathematical modeling and the simple, genetically tractable, Drosophila ovary to address open questions about how cells acquire motility, coordinate behaviors with neighboring cells, and move within an organ. In many cases communication about these behaviors between cells must occur through the extracellular space. It is unclear how extracellular signaling molecules, such as chemoattractants and cytokines, are distributed in tissues, and how spatially dependent differences in concentration may affect signaling. For example, extracellular signal, such Unpaired (UPD), can interact with the transmembrane Janus Kinase (JAK) to activate the Signal Transducer and Activator of Transcription (STAT) responsible for the cell fate motility decision. The hypothesis is that the heteromorphic extracellular domain impacts signal distribution and motile cell behaviors, which can be revealed through a hybrid agent-based model coupled to a reaction-diffusion model of extracellular signal converted to intracellular signalling and movement. Based on imaging data, we will accurately model heterogeneity in tissue structure and examine the impact of this physical constraint on molecular diffusion and signaling.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.