Building a Systems-Level View of Cell Cycle Checkpoints

构建细胞周期检查点的系统级视图

基本信息

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
项目类别：
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

项目摘要

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生长和发育的基础，而细胞的失调周期是癌症的典型，实现了对细胞周期如何控制的系统级理解现代细胞生物学最重要的目标之一。将实验生物学与数学结合起来在高度互动的协作中进行建模创建了一种强大的方法来开发全面的了解细胞周期控制。这种方法用于发现有丝分裂转变受到调节通过滞后和双稳态。下一个目标是在此基础上解决一个关键问题：如何细胞周期引擎受到外部事件的影响，特别是那些威胁细胞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 DMA 损坏，存在。失去检查点控制是几乎所有癌细胞的特征。检查站将是在从非洲爪蟾卵中提取的实验上可处理的无细胞提取物中进行了研究爪蟾胚胎，细胞周期在早期发育过程中广泛重塑。为了构建这个据了解，DNA复制检查点的数学模型将被构建并受到影响严格的实验测试。该模型应该揭示潜在的动态控制并作为预测病理和药理扰动对细胞周期影响的强大工具检查站。为了达到构建 DNA 复制检查点的系统级视图的目标，将完成以下具体目标： 1）代表不可复制效应的数学模型构建核心细胞周期引擎DNA，优化参数，建立模型在万维网上可供公众使用。 2）同步进行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并用于为模型提供信息的数据。 3)一旦了解了不可复制的DNA如何影响细胞周期引擎在手，该模型将扩展到包括 Chk1 激酶信号传导途径，癌症化疗的一个关键潜在靶点。 4）最后，模型将面临挑战准确地代表早期发育过程中 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哪里需要额外的数据。