Stochastic models of cell cycle regulation in eukaryotes

真核生物细胞周期调控的随机模型

• 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
• 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

 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（由申请人提供）：细胞周期是生长细胞复制其基因组并在分裂时将每条染色体的两个拷贝分配给两个子细胞的过程。对于生命的延续来说，这些复制（DNA合成）和分配（有丝分裂）的过程必须非常忠实地进行，这是至关重要的。在真核细胞中，DNA合成（S期）和有丝分裂（M期）在时间上被两个间隙（G1和G2）分开。如果细胞的基因组完整性以任何方式受损，则通过“检查点”阻止细胞周期的进展来强制S期和M期的适当交替。例如，如果DNA在G1期受损，检查点会阻止DNA进入S期，直到损伤得到修复。如果复制的染色体在有丝分裂纺锤体上没有正确排列，则不同的检查点阻止进入后期（姐妹染色单体分离的阶段），直到所有姐妹染色单体正确地附着到纺锤体的相反两极。检查点能够通过向控制特定细胞周期转换（G1-S，G2-M和M-G1）的分子机制发送STOP信号来阻断细胞周期进程。控制这些跃迁的分子机制具有一种特殊的性质，称为“双稳态”。在生理条件下，控制机制可以无限期地保持在两种特征状态中的任何一种：OFF状态，其对应于将细胞周期保持在过渡前阶段;以及ON状态，其对应于将细胞周期推入过渡后阶段。检查点STOP信号似乎通过将适当的开关稳定在其OFF状态来起作用。由于这些检查点对于保持生物体基因组从一代细胞到下一代细胞的完整性至关重要，因此即使在像酵母细胞（30 fL）这样小的细胞中不可避免的随机分子波动面前，它们也必须可靠地发挥作用。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，检查点功能在野生型芽殖酵母细胞中确实是强大的，但它们可能在携带特定检查点基因突变的菌株中受到损害。该提案的目的是提供所需的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运作，以及它们如何在突变细胞中失败。为了实现这一目标，将需要在随机建模和测量单个酵母细胞中的mRNA和蛋白质分子的技术方面取得新的进展。为了测试这些模型，需要专业知识来构建 并表征特定的芽殖酵母突变株的表型，所述芽殖酵母突变株由所述模型预测为在酵母mRNA和蛋白质的随机波动面前表现出检查点停滞的脆弱性。由于所有真核生物似乎都采用相同的基本分子机制来控制细胞分裂周期的进展，因此对酵母细胞中检查点操作的理解将转化为对其他类型细胞（尤其是人类细胞）中检查点功能和失败的更好理解。