Investigating the Cell Division Machinery

研究细胞分裂机制

基本信息

批准号：
10353372
负责人：
Jorge Torres
金额：
$ 39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

项目摘要

SUMMARY Cell division is a complex and specifically orchestrated set of events that culminates in the equal segregation of sister chromatids into two cells. It relies on a multitude of protein complexes, protein-protein interactions, and regulatory mechanisms driven by the activities of posttranslational modification enzymes. Misregulation of cell division can lead to unrestricted or defective cell divisions that can promote chromosomal instability and aneuploidy, which are associated with many types of cancers. Through proteomic and genetic screens we have uncovered novel proteins that are critical to the fidelity of cell division. We have applied multidisciplinary approaches that utilize cell biology, molecular biology, computational biology and biochemistry to analyze the function of these proteins. These approaches have allowed us to define the function of many new proteins with critical roles in key cell division events including centrosome homeostasis, mitotic microtubule spindle assembly, spindle assembly checkpoint function and cytokinesis. Furthermore, we have applied chemical biology approaches to define novel cell division inhibitors and their mechanisms of action, which we have used as molecular probes for dissecting the mechansims of cell division and for the development of cancer therapeutics. In this proposal, we propose to advance our understanding of the repertoire of proteins and their mechanisms that are important to cell division. This will include functional analysis of novel and poorly- characterized microtubule-associated proteins involved in centrosome homeostasis and mitotic spindle assembly, and novel components that contribute to the fidelity of the spindle assembly checkpoint. Overall, the proposed research studies will increase our understanding of the repertoire of cell division enzymes, their function whithin critical cell division events, how they are regulated, and how they coordinate with each other to ensure proper cell division. These studies will also advance our understanding of the cell division mechanisms that are dysregulated in human developmental and proliferative diseases.

概括细胞分裂是一系列复杂且专门精心策划的事件，最终导致细胞的平等分离姐妹染色单体分成两个细胞。它依赖于多种蛋白质复合物、蛋白质-蛋白质相互作用以及由翻译后修饰酶的活性驱动的调节机制。细胞失调分裂可能导致不受限制或有缺陷的细胞分裂，从而促进染色体不稳定和非整倍性，与许多类型的癌症有关。通过蛋白质组学和遗传筛选，我们发现了对细胞分裂的保真度至关重要的新蛋白质。我们应用了多学科利用细胞生物学、分子生物学、计算生物学和生物化学来分析这些蛋白质的功能。这些方法使我们能够定义许多新蛋白质的功能在关键细胞分裂事件中发挥关键作用，包括中心体稳态、有丝分裂微管纺锤体组装、纺锤体组装检查点功能和胞质分裂。此外，我们还应用化学我们使用生物学方法来定义新型细胞分裂抑制剂及其作用机制作为剖析细胞分裂机制和癌症发展的分子探针疗法。在本提案中，我们建议增进我们对蛋白质及其组成部分的理解对细胞分裂很重要的机制。这将包括新颖和较差的功能分析参与中心体稳态和有丝分裂纺锤体的微管相关蛋白特征装配，以及有助于主轴装配检查点保真度的新颖组件。总体而言，拟议的研究将增加我们对细胞分裂酶的全部知识、它们的关键细胞分裂事件中的功能、它们如何调节以及它们如何相互协调确保细胞正常分裂。这些研究还将增进我们对细胞分裂机制的理解在人类发育和增殖性疾病中失调。