Investigating the Cell Division Machinery

研究细胞分裂机制

• 批准号: 10573302
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10573302
• 关键词: Address; Aneuploidy; Biochemistry; Biology; Cell Proliferation; Cell division; Cells; Cellular biology; Centrosome; Chemicals; Chromosomal Instability; Complex; Computational Biology; Cytokinesis; Development; Disease; Ensure; Enzymes; Event; Genetic Screening; Homeostasis; Human; Malignant Neoplasms; Microtubule-Associated Proteins; Microtubules; Mitotic; Mitotic spindle; Molecular Biology; Molecular Probes; Post-Translational Protein Processing; Proteins; Proteomics; Role; Sister Chromatid; Therapeutic; cancer type; carcinogenesis; inhibitor; interdisciplinary approach; novel; novel therapeutics; protein complex; protein function; protein protein interaction; research study; segregation; Address; Aneuploidy; Biochemistry; Biology; Cell Proliferation; Cell division; Cells; Cellular biology; Centrosome; Chemicals; Chromosomal Instability; Complex; Computational Biology; Cytokinesis; Development; Disease; Ensure; Enzymes; Event; Genetic Screening; Homeostasis; Human; Malignant Neoplasms; Microtubule-Associated Proteins; Microtubules; Mitotic; Mitotic spindle; Molecular Biology; Molecular Probes; Post-Translational Protein Processing; Proteins; Proteomics; Role; Sister Chromatid; Therapeutic; cancer type; carcinogenesis; inhibitor; interdisciplinary approach; novel; novel therapeutics; protein complex; protein function; protein protein interaction; research study; segregation

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 细胞分裂是一组复杂且特殊的事件集，最终达到相等的隔离 姐妹染色单体成两个细胞。它依赖于多种蛋白质复合物，蛋白质 - 蛋白质相互作用和 翻译后修饰酶的活性驱动的调节机制。细胞的正调 分裂可以导致不受限制或有缺陷的细胞分裂，以促进染色体不稳定性和 非整倍性，与多种类型的癌症相关。通过蛋白质组学和遗传筛选我们 有发现对细胞分裂忠诚至关重要的新型蛋白质。我们已经应用了多学科 利用细胞生物学，分子生物学，计算生物学和生物化学的方法来分析 这些蛋白质的功能。这些方法使我们能够通过 在关键细胞分裂事件中的关键作用，包括中心体稳态，有丝分裂微管纺锤体 组件，主轴组件检查点功能和细胞因子。此外，我们已经申请了化学药品 定义新型细胞分裂抑制剂及其作用机制的生物学方法，我们已经使用了 作为分子探针，用于剖析细胞分裂的机甲和癌症的发展 疗法。在此提案中，我们建议促进我们对蛋白质及其曲目的理解 对细胞分裂很重要的机制。这将包括对新颖和不良的功能分析 与中心体稳态和有丝分裂纺锤体有关的微管相关蛋白的表征 组装和新颖的组件有助于纺锤体组件检查站的保真度。总体而言， 拟议的研究将增加我们对细胞分裂酶库的理解， 临界细胞分裂事件的功能，如何调节它们以及如何互相协调 确保正确的细胞分裂。这些研究还将提高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的。