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Hybrid mathematical modeling for cell fate determination in clustered cell migration

集群细胞迁移中细胞命运决定的混合数学模型

基本信息

批准号：
1953423
负责人：
Bradford Peercy
金额：
$ 37.23万
依托单位：
University of Maryland Baltimore County
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1953423&HistoricalAwards=false
关键词：
Hybrid mathematical modeling cell fate

项目摘要

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.

细胞的命运可以说是生命最基本的组成部分，它由许多因素决定，其中既有内在动力，也有外部影响。随着细胞在群落中的生长，差异就会出现，角色就会确立。不同的角色是如何确定的？在做出决定时，最重要的影响是什么？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？数学寻求发现模式，对注定要在集群中迁移和移动的细胞进行数学建模，将描述内在和外在信号之间的平衡。在那些在实验中难以形象化且随时间变化的领域，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，最终促进正常发育和阻止恶性生长。这项研究还将培训不同的研究人员，以履行他们在科学发现中的角色。成功的细胞迁移对人类发育、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推移在体内复杂的组织环境中导航的知识存在许多空白。这个项目将利用数学建模和简单的、遗传上易驯化的果蝇卵巢来解决关于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公开问题。在许多情况下，细胞之间关于这些行为的交流必须通过细胞外空间进行。目前尚不清楚细胞外信号分子，如化学诱导剂和细胞因子是如何在组织中分布的，以及浓度的空间相关性差异如何影响信号传递。例如，细胞外信号，如未配对的(UPD)，可以与跨膜Janus Kinase(JAK)相互作用，激活负责决定细胞命运的信号转导和转录激活因子(STAT)。假设是异形的胞外区影响信号的分布和细胞的运动行为，这可以通过一个基于混合试剂的模型来揭示，该模型与细胞外信号转化为细胞内信号和运动的反应-扩散模型相耦合。基于成像数据，我们将准确地模拟组织结构的异质性，并检查这种物理约束对分子扩散和信号的影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。