Mathematical modeling of cellular signaling systems

项目摘要 这个项目解决的重要挑战是获得对监管的机械性理解 严密控制细胞内信号通路时空动态的元件。相遇 在这个挑战中，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响应 它们所处环境的变化。环境因素，如激素、营养素或身体压力 由细胞表面的受体检测。然后处理该信息并将其传输到 通过细胞内信号通路调节细胞的适当区域。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 肌动蛋白细胞骨架在空间和时间上的动力学。这项任务是通过使用 在多个时间和空间尺度上作用的反馈和前馈循环。因为这些 调节环路使信号通路固有的非线性，需要数学模型来 了解这些系统的紧急特性。我们已经确定了三个细胞过程 进行系统层面的分析，为我们今后五年的研究奠定基础：1) 酿酒酵母及相关真菌在交配和萌发过程中的定向生长，2) 吞噬作用，即细胞感知和摄取细菌和其他物体的过程，以及3) 一组细胞作为一个整体移动的集体迁移。这些项目代表了 为我的实验室延续已建立的合作关系和令人兴奋的新方向。我们将继续我们的 与丹尼尔·卢博士(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应的机制。在一个新的 与艾米·格拉德菲尔特博士(北卡罗来纳大学，生物学)合作，我们将调查类似的机制是否在 出芽短梗霉在建立多极性位点中的作用。我们也会 继续我们与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图案形成的机制。最后，我们有 最近与Scott Magness博士(北卡罗来纳大学，BME)建立了一个新的合作伙伴关系，以研究上皮细胞 集体迁徙期间的两极分化。我们调查的目标是产生真正的预测性 体内细胞过程的模型，最终为深入了解该病的病因和治疗提供了线索 人类疾病。

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.