Building a Systems-Level View of Cell Cycle Checkpoints

因为细胞周期是所有真核生物生长和发育的基础， 细胞周期是典型的癌症，实现了系统水平的了解，细胞周期是如何控制的行列 现代细胞生物学中最重要的目标之一。实验生物学与数学配对 在高度交互式的协作中建模创建了一种强大的方法， 了解细胞周期控制。这种方法被用来发现有丝分裂转换是受调控的， 通过滞后和双稳态。下一个目标是在此基础上解决一个关键问题： 电池循环发动机受到外部事件的影响，特别是那些威胁电池完整性的事件。 基因组当基因组稳定性受到威胁时，检查点会阻止细胞周期，例如未复制或 损坏的DMA，存在。检查点控制的丧失是几乎所有癌细胞的特征。检查站将 研究了实验上易处理的无细胞提取物来自非洲爪蟾卵和 非洲爪蟾胚胎，在早期发育过程中细胞周期广泛重塑。建造这 理解，DNA复制检查点的数学模型将被构建并经受 严格的实验测试。这个模型应该揭示潜在的动态控制，并作为一个 预测病理学和药理学扰动对细胞周期影响的有力工具 检查站为了实现构建DNA复制检查点的系统级视图的目标， 具体目标是：1）建立一个数学模型，表示不可重复的影响， 将构建核心细胞周期引擎上的DNA，优化参数， 在万维网上供公众使用。2)同时，关键的定量实验 关于核浓度和细胞周期酶如何影响DNA复制检查点， 进行和用于通知模型的数据。3)一旦这种关于不可复制的DNA 影响细胞周期引擎是在手，该模型将扩展到包括Chk1激酶信号转导 途径，癌症化疗药物的关键潜在靶点。4)最后，该模型将受到挑战， 准确地代表了早期发育过程中DNA复制检查点的三种不同行为， 为模型提供生理测试用例，并告知需要额外数据的地方。

Because the cell cycle underlies the growth and development of all eukaryotes, and misregulation of the cell cycle typifies cancers, achieving a systems-level understanding of how the cell cycle is controlled ranks among the most important goals in modern cell biology. Pairing experimental biology with mathematical modeling in a highly interactive collaboration creates a powerful approach to develop a comprehensive understanding of cell cycle control. This approach was used to discover that mitotic transitions are regulated by hysteresis and bistability. The next goal is to build on this foundation by addressing a critical issue: how the cell cycle engine is affected by external events, in particular, those events that threaten the integrity of the genome. Checkpoints arrest the cell cycle when a threat to genomic stability, such as unreplicated or damaged DMA, exists. Loss of checkpoint control characterizes nearly all cancer cells. Checkpoints will be investigated in the experimentally tractable cell-free extracts derived from eggs of Xenopus laevis and in Xenopus embryos, where the cell cycle extensively remodels during early development. To build this understanding, a mathematical model of the DNA replication checkpoint will be constructed and subjected to rigorous experimental testing. This model should reveal underlying dynamical controls and serve as a powerful tool for predicting the effect of pathologic and pharmacologic perturbations upon cell cycle checkpoints. To reach the goal of constructing a systems-level view of the DNA replication checkpoint, the following specific aims will be completed: 1) A mathematical model representing the effect of unreplicated DNA on the core cell cycle engine will be constructed, parameters will be optimized, and the model will be made available for public use on the World Wide Web. 2) Concurrently, key quantitative experiments concerning how nuclear concentration and cell cycle enzymes impact the DNA replication checkpoint will be conducted and data used to inform the model. 3) Once this fundamental view of how unreplicated DNA affects the cell cycle engine is in hand, the model will be extended to include the Chk1 kinase signaling pathway, a key potential target for cancer chemotherapeutics. 4) Finally, the model will be challenged to accurately represent three distinct behaviors of the DNA replication checkpoint during early development, providing a physiologic test case for the model and informing where additional data are needed.