Regulation of Chromosome Segregation in Human Cells

描述（由申请人提供）：这项资助的长期目标是阐明维持染色体分离准确性的分子和机制。这些信息对于维持和改善人类健康至关重要，因为不准确的分离会导致非整倍体，并导致唐氏综合症和癌症等疾病。为了便于解剖这个和其他复杂的生物过程，我们的实验室已经开发了新的方法，通过同源重组精确地删除或修改人类体细胞中的基因。通过将这些方法与高分辨率显微镜和化学遗传学相结合，我们已经确定了蛋白激酶Plk1 （polo样激酶1）和Mps1的新功能和调控，它们是所有真核生物有丝分裂和细胞分裂的重要调节因子。基于我们的初步研究结果，我们提出了下一个资助期的三个目标：(1)阐明plk1依赖性中心体成熟的影响因素和机制；(2)检测Mps1对纺锤体组装检查点（SAC）的细胞质分支和着丝酶依赖分支的贡献；(3)鉴定Mps1的底物介导该激酶在SAC执行和染色体双向定位中的功能。这些研究将阐明调节和维持人类染色体分离高保真度的机制。这些信息对于理解正常细胞如何避免非整倍体及其对人类健康的不利影响，以及在疾病背景下开发专门针对非整倍体的新治疗方法至关重要。

DESCRIPTION (provided by applicant): The long-term goal of this grant is to elucidate the molecules and mechanisms that sustain the accuracy of chromosome segregation. Such information is crucial for maintaining and improving human health, as inaccurate segregation causes aneuploidy and contributes to disorders like Down Syndrome and cancer. To facilitate the dissection of this and other complex biological processes, our laboratory has developed novel methods for precisely deleting or modifying genes in human somatic cells via homologous recombination. By combining these methods with high-resolution microscopy and chemical genetics, we have identified novel functions and regulation of the protein kinases Plk1 (Polo-like kinase 1) and Mps1, which are essential regulators of mitosis and cell division in all eukaryotes. Based on our preliminary findings, three aims are proposed for the next grant period: (1) to elucidate the effectors and mechanism of Plk1-dependent centrosome maturation; (2) to test Mps1's contribution to the cytosolic and kinetochore-dependent branches of the spindle assembly checkpoint (SAC); and (3) to identify the substrates of Mps1 that mediate the kinase's functions in SAC enforcement and chromosome bi-orientation. These studies will illuminate the mechanisms that regulate and sustain the high fidelity of chromosome segregation in humans. Such information is crucial for understanding how normal cells avoid aneuploidy and its adverse impacts on human health, and for developing novel treatments that specifically target aneuploidy in the context of disease.