Mathematical modeling of cellular signaling systems

细胞信号系统的数学建模

基本信息

批准号：
10443561
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
项目类别：
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

项目摘要

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，采用定量实验方法来理解复杂的细胞行为。特别是，我们研究细胞过程，例如细胞命运决策，极性由细胞内信号网络协调的建立和梯度感应。目标我们的研究是了解这些网络如何充当集成系统。数学需要建模以了解协调的反馈和喂养前向调节需要信号通路的时空动力学和计算图像分析以提取来自实时图像的定量信息需要告知和验证模型。我们用来研究细胞信号的主要模型生物是酿酒酵母的酵母菌。我们的研究将微流体技术与活细胞显微镜相结合，以观察细胞行为控制良好的环境。这项工作与我们长期存在的实验室一起进行合作者Drs。 Beverly Merrede，Daniel Lew和Henrik Dohlman。实验室已建立的项目包括：1）了解与细胞极性和梯度感应有关的分子机制以及2）识别动态调节基因表达和命运决策的信号传导基序。令人兴奋的实验室的新方向是研究衰老对细胞信号传导的影响。我的实验室也参与了协作项目，以研究哺乳动物细胞中的细胞信号传导以及如何失调这些途径导致人类疾病。实验室中的当前项目包括：1）长期存在与理查德·布歇（Richard Boucher）博士合作，了解嘌呤能信号如何保持气道表面液体稳态，在囊性纤维化中失调，2）一个新项目，我们已建立合作者克劳斯·哈恩（Klaus Hahn）博士了解吞噬作用期间协调信号的机制 3）与Ned Sharpless博士一起的一个新项目，以了解调节细胞的机制造血期间的分化。所有这些项目的统一主题是使用数学建模以了解反馈和反馈法规如何产生协调时空行为。我们调查的最终目标是生成真正的预测模型可以应用于新治疗策略的基本原理设计的体内细胞过程。呢