A Systems Biology Analysis of Spindle Checkpoint Signaling

描述（由申请方提供）：非整倍性是癌细胞的一个标志，其中染色体由于异常有丝分裂而在子细胞之间不适当地分配。有丝分裂纺锤体检查点通常确保每次细胞分裂期间染色体的忠实分离，该检查点延迟后期的开始，直到每个染色体都成功地附着到纺锤体上。有丝分裂检查点的缺陷降低基因组稳定性并促进非整倍体。有丝分裂纺锤体检查点是高度稳健的，因为单个不适当附着的动粒足以阻断细胞周期进程并在中期产生可持续的有丝分裂停滞。一旦实现适当的动粒附着，检查点信号传导被熄灭，允许细胞退出中期并过渡到后期。纺锤体检查点系统的触发式切换行为背后的精确机制还不是很清楚。本提案的目的是使用定量实验研究与计算建模分析相结合的系统生物学方法来测试有丝分裂纺锤体检查点信号通路中是否存在双稳态。对纺锤体检查点逻辑的系统理解对于确定药物为什么起作用以及揭示开发更有效的抗癌药物的新途径至关重要。该建议的目的是获得一个定量的理解，这一过程中使用的实验和建模相结合。 公共卫生相关性：本研究的目的是通过实验和模型相结合的方法，对有丝分裂纺锤体检查点信号通路进行定量研究。

DESCRIPTION (provided by applicant): Aneuploidy is a hallmark of cancer cells in which chromosomes are inappropriately partitioned between daughter cells due to aberrant mitosis. Faithful segregation of chromosomes during each cell division is normally ensured by the mitotic spindle checkpoint, which delays the onset of anaphase until every chromosome has successfully attached to the spindles. Defects in the mitotic checkpoint decrease genome stability and promote aneuploidy. The mitotic spindle checkpoint is highly robust as a single improperly attached kinetochore is sufficient to block cell cycle progression and generate sustainable mitotic arrest at metaphase. Once proper kinetochore attachment is achieved, checkpoint signaling is extinguished allowing the cells exit metaphase and transition into anaphase. The precise mechanisms underlying the toggle-like switching behavior of the spindle checkpoint system are not very well understood. The goal of this proposal is to test whether there is bistability in the mitotic spindle checkpoint signaling pathway using a systems biology approach combining quantitative experimental studies with computational modeling analysis. A systems understanding of the logic of spindle checkpoint is critical to determine why drugs work or not and reveal new avenues for developing more effective anti-cancer drugs. This proposal is aimed to obtain a quantitative understanding of this process using a combination of experiments and modeling. PUBLIC HEALTH RELEVANCE: This proposal is aimed to obtain a quantitative understanding of mitotic spindle checkpoint signaling pathway using a combination of experimental and modeling approach.