Building a Systems-Level View of Cell Cycle Checkpoints

构建细胞周期检查点的系统级视图

• 批准号: 7571659
• 负责人: JILL C SIBLE
• 金额: $ 22.22万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-06 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571659
• 关键词: Address; Affect; Agreement; Area; Behavior; Biochemical; Biological Models; Biology; Cell Cycle; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cells; Cellular biology; Checkpoint kinase 1; Collaborations; Complex; Cyclins; DNA; DNA biosynthesis; Data; Development; Disease; Embryo; Environment; Enzymes; Eukaryota; Eukaryotic Cell; Event; Foundations; Genome; Genome Stability; Genomics; Goals; Growth and Development function; Hand; Internet; Intervention; Knowledge; Malignant Neoplasms; Maturation-Promoting Factor; Measures; Mitosis; Mitotic; Modeling; Modification; Molecular; Mutation; Nuclear; Pathologic; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Problem Solving; Process; Rana; Relative (related person); Reproduction; Research Personnel; Signal Pathway; Somatic Cell; System; Testing; Therapeutic Intervention; Time; Work; Xenopus; Xenopus laevis; cancer cell; design; egg; embryo cell; forging; mathematical model; novel; research study; response; theories; tool

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.

因为细胞周期是所有真核生物的生长和发展的基础 循环代表癌症，实现对细胞周期如何控制等级的系统级别的理解 现代细胞生物学中最重要的目标之一。将实验生物学与数学配对 在高度互动的协作中建模创造了一种有力的方法来开发全面 了解细胞周期控制。这种方法用于发现有丝分裂过渡是调节的 通过磁滞和双重性。下一个目标是通过解决一个关键问题来建立基础： 细胞周期引擎受外部事件的影响，尤其是那些威胁到完整性的事件 基因组。当对基因组稳定性的威胁（例如未复制或 损坏的DMA，存在。几乎所有癌细胞的检查点控制损失都表征了所有癌细胞。检查站将是 在源自Xenopus laevis卵和在 爪蟾胚胎，其中细胞周期在早期发育过程中进行了广泛的重塑。建立这个 理解，将构建DNA复制检查点的数学模型并进行 严格的实验测试。该模型应揭示潜在的动力控制，并用作 预测病理和药理扰动对细胞周期的影响的强大工具 检查点。为了达到构建DNA复制检查点系统级视图的目标 以下特定目的将完成：1）代表未重复的效果的数学模型 将构建核心细胞周期发动机上的DNA，将优化参数，模型将为 可在万维网上公开使用。 2）同时，关键定量实验 关于核浓度和细胞周期酶如何影响DNA复制检查点将是 进行和用于告知模型的数据。 3）曾经对未复制DNA的基本观点 影响细胞周期发动机在手中，该模型将扩展到包括CHK1激酶信号传导 途径，是癌症化学治疗剂的关键潜在靶标。 4）最后，该模型将受到挑战 准确地代表了早期开发过程中DNA复制检查点的三种不同行为， 为模型提供生理测试用例，并告知需要其他数据。

项目成果

A quantitative model of the effect of unreplicated DNA on cell cycle progression in frog egg extracts.

• DOI: 10.1016/j.jtbi.2009.05.018
• 发表时间: 2009-09-07
• 期刊: JOURNAL OF THEORETICAL BIOLOGY
• 影响因子: 2
• 作者: Zwolak, Jason;Adjerid, Nassiba;Bagci, Elife Z.;Tyson, John J.;Sible, Jill C.
• 通讯作者: Sible, Jill C.