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; 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.

项目摘要 该项目解决的重要挑战是对监管的机械理解 紧紧控制细胞内信号通路的时空动力学的元素。见面 在此挑战中，我们结合了计算方法，包括数学建模和图像 分析，通过在单细胞水平进行实验。所有细胞都必须感知并回应 他们的环境变化。荷尔蒙，营养或身体压力等环境线索是 被细胞表面的受体检测到。此信息已被处理并传输到 细胞内信号通路的适当区域。对刺激的适当反应 通常需要细胞改变形状或移动。因此，信号通路必须协调 肌动蛋白细胞骨架的动力学在时空和时间上。此任务是通过使用完成的 反馈和前馈回路，作用于多个时间和空间尺度。因为这些 调节环使信号通路固有地非线性，需要数学建模才能 了解这些系统的新兴属性。我们已经确定了三个细胞过程 在接下来的五年中借助系统级分析并为我们的研究构成基础：1） 在酵母菌S.酿酒酵母和相关真菌中的交配过程中定向生长，2） 吞噬作用，细胞感知和摄取细菌和其他物体的过程，3） 集体迁移，其中一组单元作为一个单元移动。这些项目代表 继续为我的实验室提供既定的合作和令人兴奋的新方向。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）的实验室合作了解 酿酒酵母中极性建立和梯度感测的机制。在新的 与DR，Amy Gladfelter（UNC，生物学）合作，我们将研究类似机制是否发挥作用 真菌金黄色葡萄球菌pallulans在建立多个极性位点中的作用。我们也会 继续我们与Klaus Hahn博士（UNC，药理学）实验室的长期合作 研究吞噬作用过程中空间图案的机制。最后，我们有 最近与Scott Magness博士（UNC，BME）建立了新的合作，以调查上皮 集体迁移期间的极化。我们调查的目的是产生真正的预测 体内细胞过程的模型，最终提供了有关病因和治疗的见解 人类疾病。