Mathematical modeling of cellular signaling systems

细胞信号系统的数学建模

• 批准号: 10179426
• 负责人: Timothy C Elston
• 金额: $ 45.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179426
• 关键词: Animal Model; Behavior; Cell Differentiation process; Cell Polarity; Cell model; Cell physiology; Cells; Collaborations; Complex; Computing Methodologies; Controlled Environment; Cystic Fibrosis; Development; Disease; Feedback; Gene Expression; Goals; Heart Diseases; Hematopoiesis; Homeostasis; Human; Image Analysis; Investigation; Malignant Neoplasms; Mammalian Cell; Modeling; Molecular; Pathway interactions; Phagocytosis; Regulation; Research; Saccharomyces cerevisiae; Signal Pathway; Signal Transduction; System; Techniques; Therapeutic; Work; Yeasts; age effect; airway surface liquid; cell behavior; design; human disease; in vivo Model; live cell imaging; live cell microscopy; mathematical model; microfluidic technology; novel therapeutic intervention; predictive modeling; spatiotemporal

This project seeks to integrate computational methods, including mathematical modeling and image analysis techniques, with quantitative experimental approaches to understand complex cellular behavior. In particular, we investigate cellular processes, such as cell fate decisions, polarity establishment, and gradient sensing, that are coordinated by intracellular signaling networks. The goal of our research is to understand how these networks function as integrated systems. Mathematical modeling is needed to understand the feedback and feed forward regulation that coordinates the spatiotemporal dynamics of signaling pathways, and computational image analysis is needed to extract the quantitative information from live-cell images that is required to inform and validate the models. The primary model organism we use to study cell signaling is the yeast Saccharomyces cerevisiae. Our investigations combine microfluidic technology with live-cell microscopy to observe cellular behavior in well-controlled environments. This work is performed together with the labs of our longstanding collaborators Drs. Beverly Errede, Daniel Lew and Henrik Dohlman. Established projects in the lab include: 1) understanding molecular mechanisms involved in cell polarity and gradient sensing and 2) identifying signaling motifs that dynamically regulate gene expression and fate decisions. An exciting new direction for the lab is to investigate the effects of aging on cell signaling. My lab is also involved in collaborative projects to investigate cell signaling in mammalian cells and how the dysregulation of these pathways leads to human disease. Current projects in the lab include: 1) a longstanding collaboration with Dr. Richard Boucher to understand how purinergic signaling maintains airway surface liquid homeostasis and is dysregulated in cystic fibrosis, 2) a new project with our established collaborator Dr. Klaus Hahn to understand mechanisms that coordinate signaling during phagocytosis and 3) a new project with Dr. Ned Sharpless to understand the mechanisms that regulate cell differentiation during hematopoiesis. The unifying theme of all these projects is the use of mathematical modeling to understand how feedback and feed forward regulation generates coordinated spatiotemporal behavior. The ultimate goal of our investigations is to generate truly predictive models of in vivo cellular processes that can be applied to the rationale design of new therapeutic strategies. !

该项目旨在整合计算方法，包括数学建模和图像 分析技术，定量实验方法，以了解复杂的细胞 行为特别是，我们研究细胞过程，如细胞命运的决定，极性 建立和梯度传感，这是由细胞内信号网络协调。目标 我们研究的重点是了解这些网络如何作为集成系统发挥作用。数学 需要建模来理解协调 信号通路的时空动力学，需要计算机图像分析来提取 来自活细胞图像的定量信息，这是为模型提供信息和验证所需的。 我们用来研究细胞信号传导的主要模式生物是酵母酿酒酵母。我们 研究联合收割机微流控技术和活细胞显微镜观察细胞行为 良好的控制环境。这项工作是与我们长期以来的实验室一起进行的 合作者Beverly Errede博士、丹尼尔卢博士和亨利克多尔曼博士。实验室中的既定项目 包括：1）了解细胞极性和梯度感应的分子机制，2） 识别动态调节基因表达和命运决定的信号基序。一个令人兴奋 实验室的新方向是研究衰老对细胞信号的影响。我的实验室也参与了 研究哺乳动物细胞中的细胞信号传导以及 这些途径导致人类疾病。实验室目前的项目包括：1）一个长期的 与Richard Boucher博士合作，了解嘌呤能信号如何维持气道表面 囊性纤维化中液体稳态和失调，2）我们建立的一个新项目 合作者Klaus Hahn博士，以了解吞噬作用期间协调信号传导的机制 和3）与Ned Sharpless博士合作的一个新项目，以了解调节细胞的机制， 造血过程中的分化。所有这些项目的统一主题是使用数学 建模以了解反馈和前馈调节如何产生协调的 时空行为我们研究的最终目标是生成真正的预测模型， 体内细胞过程，可以应用于新的治疗策略的基本原理设计。 !