Mathematical modeling of cellular signaling systems

细胞信号系统的数学建模

• 批准号: 10623845
• 负责人: Timothy C Elston
• 金额: $ 46.73万
• 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 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623845
• 关键词: Actins; Address; Bacteria; Biology; Cancer Biology; Cell model; Cell physiology; Cell surface; Cells; Collaborations; Cues; Cytoskeleton; Development; Disease; Environment; Epithelium; Etiology; Feedback; Goals; Growth; Heart Diseases; Hormones; Human; Image Analysis; Ingestion; Investigation; Malignant Neoplasms; Nutrient; Partner in relationship; Pattern; Phagocytosis; Pharmacology; Process; Property; Regulatory Element; Saccharomyces cerevisiae; Shapes; Signal Pathway; Signal Transduction; Site; Stimulus; Stress; System; Therapeutic; Time; Yeasts; experimental study; fungus; human disease; in vivo Model; insight; mathematical model; migration; predictive modeling; pullulan; rational design; receptor; response; spatiotemporal; transmission process

Project Summary The important challenge this project addresses is to gain a mechanistic understanding of regulatory elements that tightly control the spatiotemporal dynamics of intracellular signaling pathways. To meet this challenge, we combine computational approaches, including mathematical modeling and image analysis, with experiments performed at the single cell level. All cells must sense and respond to changes in their environment. Environmental cues such as hormones, nutrients or physical stresses are detected by receptors on the cell surface. This information is than processed and transmitted to appropriate regions of the cell by intracellular signaling pathways. The proper response to a stimulus often requires cells to change shape or move. Therefore, signaling pathways must coordinate the dynamics of the actin cytoskeleton in both space and time. This task is accomplished through the use of feedback and feedforward loops acting over multiple temporal and spatial scales. Because these regulatory loops make signaling pathways inherently nonlinear, mathematical modeling is required to understand the emergent properties of these systems. We have identified three cellular processes that lend themselves to systems-level analysis and form the basis for our studies over the next five years: 1) directed growth during mating and budding in the yeast S. cerevisiae and related fungi, 2) phagocytosis, the process through which cells sense and ingest bacteria and other objects, and 3) collective migration in which a group of cells move as a single unit. These projects represent the continuation of established collaborations and exciting new directions for my lab. We will continue our collaboration with the lab of Dr. Daniel Lew (Duke, Pharmacology and Cancer Biology) to understand the mechanisms that underlie polarity establishment and gradient sensing in S. cerevisiae. In a new collaboration with Dr, Amy Gladfelter (UNC, Biology), we will investigate if similar mechanisms play a role in the establishment of multiple polarity sites by the fungus Aureobasidium pullulans. We also will continue our long-standing collaboration with the lab of Dr. Klaus Hahn (UNC, Pharmacology) to investigate the mechanisms that underlie spatial patterning during phagocytosis. Finally, we have recently established a new collaboration with Dr. Scott Magness (UNC, BME) to investigate epithelial polarization during collective migration. The goal of our investigations is to generate truly predictive models of in vivo cellular processes that ultimately provide insights into the etiology and treatment of human diseases.

项目概要 该项目面临的重要挑战是获得对监管的机械理解 严格控制细胞内信号通路时空动态的元件。见面 针对这一挑战，我们结合了计算方法，包括数学建模和图像 分析，在单细胞水平上进行实验。所有细胞都必须感知并做出反应 他们的环境发生变化。激素、营养物质或身体压力等环境因素 由细胞表面的受体检测到。该信息随后被处理并传输至 通过细胞内信号通路作用于细胞的适当区域。对刺激的正确反应 通常需要细胞改变形状或移动。因此，信号通路必须协调 肌动蛋白细胞骨架在空间和时间上的动力学。这个任务是通过使用来完成的 在多个时间和空间尺度上起作用的反馈和前馈循环。因为这些 调节环路使信号通路本质上是非线性的，需要数学建模来 了解这些系统的新兴特性。我们已经确定了三个细胞过程 适合系统级分析，并构成我们未来五年研究的基础：1） 酿酒酵母和相关真菌在交配和出芽过程中的定向生长，2) 吞噬作用，细胞感知和摄取细菌和其他物体的过程，以及 3) 集体迁移，其中一组细胞作为一个单元移动。这些项目代表了 继续已建立的合作并为我的实验室带来令人兴奋的新方向。我们将继续我们的 与 Daniel Lew 博士（杜克大学药理学和癌症生物学）实验室合作，了解 酿酒酵母极性建立和梯度传感的机制。在一个新的 与 Amy Gladfelter 博士（北卡罗来纳大学生物学）合作，我们将研究类似的机制是否发挥作用 出芽短梗霉在建立多个极性位点中的作用。我们也会 继续与 Klaus Hahn 博士（北卡罗来纳大学药理学）实验室的长期合作 研究吞噬过程中空间模式的机制。最后，我们有 最近与 Scott Magness 博士（UNC、BME）建立了新的合作关系，以研究上皮细胞 集体迁移过程中的两极分化。我们调查的目标是产生真正的预测 体内细胞过程模型，最终提供对病因和治疗的见解 人类疾病。

项目成果

Gradient Tracking by Yeast GPCRs in a Microfluidics Chamber.

• DOI: 10.1007/978-1-0716-1221-7_18
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Suzuki SK;Kelley JB;Elston TC;Dohlman HG
• 通讯作者: Dohlman HG

Orientation of Cell Polarity by Chemical Gradients.

• DOI: 10.1146/annurev-biophys-110821-071250
• 发表时间: 2022-05-09
• 期刊: ANNUAL REVIEW OF BIOPHYSICS
• 影响因子: 12.4
• 作者: Ghose, Debraj;Elston, Timothy;Lew, Daniel
• 通讯作者: Lew, Daniel

Stochastic modeling of human papillomavirusearly promoter gene regulation.

人乳头瘤病毒早期启动子基因调控的随机模型。

• DOI: 10.1016/j.jtbi.2019.110057
• 发表时间: 2020
• 期刊: Journal of theoretical biology
• 影响因子: 2
• 作者: Giaretta,Alberto;Toffolo,GiannaMaria;Elston,TimothyC
• 通讯作者: Elston,TimothyC

A predictive model of gene expression reveals the role of network motifs in the mating response of yeast.

• DOI: 10.1126/scisignal.abb5235
• 发表时间: 2021-02-16
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Pomeroy AE;Peña MI;Houser JR;Dixit G;Dohlman HG;Elston TC;Errede B
• 通讯作者: Errede B

Bistability in the polarity circuit of yeast.

酵母极性电路的双稳定性。

• DOI: 10.1091/mbc.e20-07-0445
• 发表时间: 2021
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Errede,Beverly;Hladyshau,Siarhei;Nivedita,Nivedita;Tsygankov,Denis;Elston,TimothyC
• 通讯作者: Elston,TimothyC