Stochastic models of cell cycle regulation in eukaryotes

真核生物细胞周期调控的随机模型

基本信息

批准号：
9059125
负责人：
Jean M Peccoud
金额：
$ 50.63万
依托单位：
COLORADO STATE UNIVERSITY
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：
2006-06-06 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9059125
关键词：
Accounting Anaphase Architecture Biological Biological Process Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Regulation Cell Proliferation Cell division Cell physiology Cells Cellular biology Characteristics Chromosomes DNA DNA Damage DNA biosynthesis Data Disease Elements Ensure Etiology Eukaryota Eukaryotic Cell Event Exhibits Failure Fluorescence Microscopy G1 Phase G1/S Transition Gene Expression Generations Genes Genome Genomic Instability Goals Growth Growth and Development function Health Human Indium Individual Life Literature Malignant Neoplasms Mammalian Cell Measurement Measures Messenger RNA Metaphase Methods Mitosis Mitotic spindle Mitotic/Spindle Checkpoint Modeling Molecular Molecular Biology Molecular Models Molecular Probes Monitor Mutation Noise Normal Cell Organism Phase Phase Transition Phenotype Physiological Play Positioning Attribute Process Property Proteins Publications Replication-Associated Process Reproduction Role S Phase Saccharomyces cerevisiae Saccharomycetales Series Signal Transduction Sister Chromatid System Technology Testing Time Translating Uncertainty Ursidae Family Yeasts base cancer cell cell growth cell type data acquisition daughter cell experimental analysis genome integrity imaging platform improved innovation mathematical model molecular modeling mutant operation prevent repaired response theories tool transmission process tumor progression

项目摘要

DESCRIPTION (provided by applicant): The cell cycle is the process by which a growing cell replicates its genome and partitions the two copies of each chromosome to two daughter cells at division. It is of utmost importance to the perpetuation of life that these processes of replication (DNA synthesis) and partitioning (mitosis) be carried out with great fidelity. In eukaryotic cells, DNA synthesis (S phase) and mitosis (M phase) are separated in time by two gaps (G1 and G2). Proper alternation of S phase and M phase is enforced by `checkpoints' that block progression through the cell cycle if the genomic integrity of the cell is compromised in any way. For example, if DNA is damaged in G1 phase a checkpoint blocks progression into S phase until the damage can be repaired. If replicated chromosomes are not properly aligned on the mitotic spindle, a different checkpoint blocks progression into anaphase (the phase of sister chromatid separation) until all sister chromatids are properly attached to opposite poles of the spindle. Checkpoints are able to block cell cycle progression by sending a STOP signal to the molecular mechanisms that govern specific cell-cycle transitions (G1-S, G2-M, and M-G1). The molecular mechanisms that govern each of these transitions have a peculiar property called `bistability.' Under physiological conditions, the control mechanism can persist indefinitely in either of two characteristic states: the OFF state, which corresponds to holding the cell cycle in the pre-transition phase; and the ON state, which corresponds to pushing the cell cycle into the post-transition phase. Checkpoint STOP signals seem to act by stabilizing the appropriate bistable switches in its OFF state. Because these checkpoints are crucial to maintaining the integrity of an organism's genome from one generation of cells to the next, it is vital that they function reliably even in the face of random molecular fluctuations that are inevitable in a cell a small as a yeast cell (30 fL). Calculations based on stochastic models of the molecular mechanisms governing cell cycle progression suggest that checkpoint functions are indeed robust in wild-type budding yeast cells, but they may be compromised in strains carrying mutations of specific checkpoint genes. The purpose of this proposal is to provide the mathematical models and experimental data needed to understand how cell cycle checkpoints operate reliably in wild-type yeast cells and how they fail in mutant cells. To reach this goal wil require new advances in stochastic modeling and in the technology of measuring mRNA and protein molecules in single yeast cells. To test the models will require the expertise to construct and characterize the phenotypes of specific mutant strains of budding yeast that are predicted by the model to exhibit fragility of checkpoint arrest in the face of random fluctuations in yeast mRNAs and proteins. Because all eukaryotic organisms seem to employ the same fundamental molecular machinery that governs progression through the cell division cycle, the understanding of checkpoint operations in yeast cells will translate into a better understanding of checkpoint functions and failures in other types of cells, most notably human cells.

描述（由适用提供）：细胞周期是生长细胞复制其基因组并将每个染色体的两个副本分配给分裂处的两个子细胞的过程。对于生命的延续至关重要的是，这些复制过程（DNA合成）和分区（有丝分裂）的忠诚度很高。在真核细胞中，DNA合成（S相）和有丝分裂（M相）在时间上分离有两个间隙（G1和G2）。如果细胞的基因组完整性以任何方式损害，则可以通过“检查点”的“检查点”来执行S相和M相的适当替代方案。例如，如果DNA在G1阶段中受损，则A检查点会阻止进程到S相，直到可以修复损伤为止。如果在有丝分裂主轴上无法正确对齐，则不同的检查点会阻止进展到后期（姐妹染色单体分离的阶段，直到所有姐妹染色体都适当地连接到纺锤体的相对杆上。检查点能够通过将停止信号传递给分子机动化（分子g2），以阻止细胞循环，该细胞循环（用于跨越的细胞），该细胞及其分子的机动化（g2）g2 secliss and trience and comption g2 gycular gg2 gycular gycular gg2 gg2 g ys g g ys g2 m-g1。双态切换处于关闭状态，因为这些检查点对于维持一个生物体的基因组的完整性至关重要，从一代细胞到下一个细胞至关重要，即使面对随机的分子波动，它们在不可避免的细胞中也可以可靠地发挥作用。基于控制细胞周期进程的分子机制的随机模型的计算表明，检查点功能确实在野生型芽芽的酵母菌细胞中确实很强，但在携带特定检查点基因突变的菌株中可能会损害它们。该建议的目的是提供数学模型和实验数据，以了解细胞周期检查点如何在野生型酵母细胞中可靠地工作以及它们在突变细胞中的失败。为了实现这一目标，将需要在随机建模和测量单酵母细胞中测量mRNA和蛋白质分子的技术方面取得新的进步。测试模型将需要专业知识来构建并表征了该模型预测的发芽酵母特异性突变菌株的表型在面对酵母mRNA和蛋白质中随机波动时表现出脆弱性的脆弱性。因为所有真核生物似乎都采用了控制通过细胞分裂周期发展的相同基本分子机制，所以对酵母细胞中检查点操作的理解将转化为对检查点功能和其他类型细胞（最明显的人类细胞）中的检查点功能和失败。