Organization of the Mammalian Mitotic Spindle

准确的染色体分离对于物种的繁殖和细胞的活力是必需的， 由一个叫做纺锤体的复杂微管结构驱动。密集的生化，遗传，和 蛋白质组学研究提供了参与纺锤体组织的蛋白质的广泛目录， 纺锤体依赖的染色体运动。然而，这些努力并没有揭示分子机制 确保哺乳动物细胞中染色体的可靠分离。最近，我们发现， 人类肿瘤细胞中染色体错误分离的常见原因是动粒的持续存在， 微管（K-MT）附着错误。这表明，确保忠诚的最重要机制 染色体分离是对k-MT附着稳定性的微调，但我们对k-MT如何附着稳定性的理解， 有丝分裂期间调节的附着稳定性完全不完全。我们不明白 稳定和去稳定组分协同工作，以产生一致的k-MT附着稳定性， 有丝分裂的不同阶段。我们也不知道非整倍性如何影响基因组的稳定性和细胞 生存基于当前融资期内生成的模型， 资助期，以结合联合收割机生化方法和活细胞成像测试模型，并确定 有丝分裂中K-MT附着的调节机制。了解这些机制可能会导致 to new新therapeutic治疗approaches方法for cancer癌症treatment治疗. 相关性（参见说明）： 染色体分离错误导致非整倍体，从而导致出生缺陷，通常与 晚期癌症患者这里提出的实验的目标是鉴定蛋白质， 确定人类细胞中高保真染色体分离的机制。数据 从这项工作中产生的将提供深入了解肿瘤细胞中的非整倍体机制，并可能揭示 染色体不稳定非整倍体肿瘤的治疗策略。

Accurate chromosome segregation is essential for the propagation of species and the viability of cells, and is driven by a complex microtubule-based structure called the spindle. Intensive biochemical, genetic, and proteomic efforts provide an extensive catalogue of proteins that participate in spindle organization and spindle-dependent chromosome movement. However, these efforts don't reveal the molecular mechanisms that ensure faithful chromosome segregation in mammalian cells. Recently, we showed that the most common cause of chromosome mis-segregation in human tumor cells is the persistence of kinetochore- microtubule (k-MT) attachment errors. This indicates that the most important mechanism ensuring faithful chromosome segregation is the fine-tuning of k-MT attachment stability, yet our understanding for how k-MT attachment stability is regulated during mitosis is starkly incomplete. We don't understand how the stabilizing and destabilizing components work in concert to generate a coherent k-MT attachment stability at different phases of mitosis. We also don't understand how aneuploidy influences genome stability and cell survival. Based on models generated during the current funding period, it is our goal in the forthcoming funding period to combine biochemical methods and live cell imaging to test models and determine the mechanisms of the regulation of K-MT attachments in mitosis. Understanding these mechanisms could lead to new therapeutic approaches for cancer treatment. RELEVANCE (See instructions): Errors in chromosome segregation cause aneuploidy that causes birth defects and is commonly associated with advanced stage cancer. The goal of the experiments proposed here is to identify the proteins and determine the mechanisms responsible for high fidelity chromosome segregation in human cells. Data generated from this work will provide insight into mechanisms of aneuploidy in tumor cells and may reveal strategies for therapy of chromosomally unstable aneuploid tumors.