Mathametical modeling of cell fate transitions regulated by ultra-feedbacks

超反馈调节细胞命运转变的数学模型

• 批准号: 10221005
• 负责人: Tian Hong
• 金额: $ 20万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221005
• 关键词: Address; Algebraic Geometry; Apical; Binding; Biological; Cell Fate Control; Cell Proliferation; Cell model; Cell physiology; Cells; Complex; Data; Development; Disease; Disease Progression; Embryonic Development; Ensure; Environment; Epithelial; Epithelial Cells; Family; Feedback; Fibrosis; Gene Expression Regulation; Gene Family; Genes; Goals; Information Theory; Intercellular Junctions; Intuition; Malignant Neoplasms; Mathematics; Measures; Mesenchymal; Methods; Modeling; Natural regeneration; Nature; Neoplasm Metastasis; Pathologic; Pathologic Processes; Pattern; Physiological; Population; Process; Proliferating; Property; Regenerative Medicine; Regulation; Regulator Genes; Reporting; Research; Role; Sampling; Signal Transduction; Source; Structure; System; Testing; Tissue Engineering; Transitional Epithelium; analytical method; base; cancer therapy; cell motility; cell type; cellular imaging; dynamic system; epithelial to mesenchymal transition; experimental study; genome editing; innovation; insight; live cell imaging; mathematical analysis; mathematical methods; mathematical model; multi-scale modeling; postnatal development; predictive modeling; regenerative therapy; response; simulation; success; theories; tool; transcription factor; transcriptome; transcriptomics; transdifferentiation; transmission process; tumor; wound healing

Cell fate transition (conversion between cell types) is a fundamental process critical for development and disease progression. Gene regulatory networks controlling cell fate transitions often involve positive feedback loops. Recent data suggest that highly interconnected positive feedback loops (defined as ultra- feedback circuit in this proposal) have additional functions, but the current understanding of these networks is incomplete, partly due to the lack of theories and mathematical methods to analyze such complex circuits. Epithelial-mesenchymal transition (EMT), a process in which rigid epithelial cells convert to motile mesenchymal forms, is an example of cell fate transitions that are regulated by ultra- feedback circuits. EMT occurs in both normal and pathological conditions such as metastasis. Recent discoveries suggest two complex cellular properties that make EMT difficult to understand intuitively: the formation of multiple intermediate EMT states and the partial reversibility of EMT. The functions of the ultra-feedback circuits in regulating the two cellular properties are yet to be defined. The goal of the proposed study is to gain deeper understanding of these properties of EMT by developing new methods, models and theories to characterize the ultra-feedback circuits. We will combine real algebraic geometry, stability analysis and numerical methods to identify stable steady states that arise from ultra-feedback systems, and we will apply the method to analyze the EMT spectrum of cell types. We will quantify partially reversible EMT with a new theoretical framework based on information theory and dynamical systems. Theory driven simulations and experiments will be performed to examine how ultra-feedback circuits control reversibility. We will characterize the roles of ultra-feedback circuits in cell motility and proliferation during EMT using multiscale modeling and live-cell imaging. The proposal brings about new methods to analyze a large, emerging family of dynamical systems containing a wide range of network structures, a new theoretical framework for understanding information transmission and retainment, and a new multiscale modeling framework for systems with complex state transitions and multiple sources of stochasticity. The proposed study addresses fundamental questions about the interplay between two important and emerging properties of EMT (its multistate nature and its restricted reversibility) with mathematical innovations, and it will provide critical insights into gene regulations of cell fate transitions during development and disease progression. The success of the project will lead to new quantitative information of EMT and new concepts for better understanding EMT properties and for analyzing other cell fate transitions involving ultra-feedback circuits.

细胞命运转变（细胞类型之间的转换）是对发育和发育至关重要的基本过程。 疾病进展。控制细胞命运转变的基因调控网络通常涉及积极的 反馈循环。最近的数据表明，高度相互关联的正反馈循环（定义为超 本提案中的反馈电路）有额外的功能，但目前对这些的理解 网络是不完整的，部分原因是缺乏分析此类网络的理论和数学方法 复杂的电路。上皮-间质转化（EMT），刚性上皮细胞 转化为运动间充质形式，是细胞命运转变的一个例子，受超调节 反馈电路。 EMT 发生在正常情况和病理情况（例如转移）中。最近的 研究发现表明两种复杂的细胞特性使得 EMT 难以直观地理解： 多个中间EMT状态的形成和EMT的部分可逆性。的职能 调节这两种细胞特性的超反馈电路尚待定义。的目标 拟议的研究是通过开发新方法来更深入地了解 EMT 的这些特性， 模型和理论来表征超反馈电路。我们将结合实代数几何， 稳定性分析和数值方法来识别超反馈产生的稳定状态 系统，我们将应用该方法来分析细胞类型的 EMT 谱。我们将部分量化 具有基于信息论和动力系统的新理论框架的可逆EMT。 将进行理论驱动的模拟和实验来检查超反馈电路如何 控制可逆性。我们将描述超反馈电路在细胞运动和增殖中的作用 在 EMT 期间使用多尺度建模和活细胞成像。该提案带来了新的方法 分析一个庞大的、新兴的动力系统家族，其中包含广泛的网络结构， 理解信息传输和保留的新理论框架，以及新的 用于具有复杂状态转换和多个来源的系统的多尺度建模框架 随机性。拟议的研究解决了有关两者之间相互作用的基本问题 EMT 的重要和新兴特性（其多状态性质及其有限的可逆性） 数学创新，它将为细胞命运转变的基因调控提供重要的见解 在发育和疾病进展期间。该项目的成功将带来新的量化 EMT 信息和新概念，以便更好地理解 EMT 特性和分析其他细胞 涉及超反馈电路的命运转变。