Regulation of the meiotic cell cycle

减数分裂细胞周期的调节

• 批准号: 8004059
• 负责人: ANGELIKA B AMON
• 金额: $ 27.23万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004059
• 关键词: 5' Untranslated Regions; Aneuploidy; Biological; Cell Cycle; Cell division; Cells; Chromosome Segregation; Chromosomes; Cyclin-Dependent Kinases; Cyclins; DNA biosynthesis; Down Syndrome; Ensure; Eukaryota; Event; Germ Cells; Goals; Grant; Human; Infertility; Kinetochores; Mammals; Mediating; Meiosis; Mental Retardation; Methods; Microtubules; Mitosis; Molecular; Molecular Genetics; Pathway interactions; Pattern; Phase; Process; Regulation; Saccharomyces cerevisiae; Sister Chromatid; Spontaneous abortion; Techniques; Testing; Translations; Yeasts; prevent; programs; public health relevance; segregation

DESCRIPTION (provided by applicant): Aneuploidy is the leading cause of miscarriages and mental retardation in humans. Determining the causes of meiotic chromosome mis-segregation is thus vital for understanding the principles underlying Down's Syndrome and infertility. The long- term goal of our studies is to define the mechanisms that prevent chromosome mis-segregation and thus aneuploidy during meiosis. Meiosis is a specialized cell division during which a single DNA replication phase is followed by two consecutive chromosome segregation phases (meiosis I and meiosis II). Meiosis-specific factors act on the cyclin-dependent kinase (CDK) Cdc28 associated with the six Clb cyclins (Clb-CDKs) to bring about the unique meiotic cell division program. This grant has two goals. (1) We want to characterize how Clb-CDKs control meiosis. (2) We want to characterize the changes that occur on CDKs and its regulators during meiosis and to identify the meiosis-specific regulators that cause these changes. In Specific Aim 1 we will determine the mechanisms that prevent Clb1-CDKs from being active during meiosis II and examine the importance of this regulation. In Specific Aim 2 we will investigate how translation of the cyclin CLB3 is controlled. Inhibition of CLB3 translation is essential for meiosis I chromosome segregation. Thus, understanding how CLB3 translation is controlled and how CLB3 inhibits meiosis I is essential to understand how a meiosis I chromosome segregation pattern is established. In Specific Aim 3 we will determine how CLB3 inhibits meiosis I chromosome segregation. Since the basic cell division machinery is highly conserved from yeast to human and given that most of the factors described in this proposal have also been shown to control meiosis in mammals, it is likely that the processes governing meiosis will also be conserved across species. Thus, as with many other cell cycle studies, the regulatory processes discovered and characterized in yeast will likely guide the way for studies in higher eukaryotes including human. Public Health Relevance: Aneuploidy generated during meiosis is the leading cause of mental retardation and miscarriages in humans. Determining the molecular mechanisms governing meiotic chromosome segregation and the surveillance pathways that ensure that gamete formation occurs with accuracy is thus vital for understanding the principles underlying chromosome mis-segregation leading to Down's Syndrome and infertility. The long-term goal of our studies is to define the mechanisms that control meiotic chromosome segregation and gamete formation at the molecular level.

描述（由申请人提供）：非整倍性是人类流产和智力低下的主要原因。因此，确定减数分裂染色体错误分离的原因对于理解唐氏综合症和不育的原理至关重要。我们研究的长期目标是定义防止染色体错误分离的机制，从而在减数分裂过程中定义了非整倍性。减数分裂是一种专门的细胞分裂，在此期间，单个DNA复制阶段之后是两个连续的染色体分离阶段（减数分裂I和减数分裂II）。减数分裂特异性因素对与六个CLB细胞周期蛋白（CLB-CDK）相关的细胞周期蛋白依赖性激酶（CDK）CDC28作用，以实现独特的减数分裂细胞分裂程序。该赠款有两个目标。 （1）我们想表征CLB-CDK如何控制减数分裂。 （2）我们想表征在减数分裂过程中CDK及其调节剂上发生的变化，并确定引起这些变化的减数分裂特异性调节剂。在特定目标1中，我们将确定防止CLB1-CDK在减数分裂II期间活跃的机制，并检查该调节的重要性。在特定目标2中，我们将研究如何控制细胞周期蛋白CLB3的翻译。 CLB3翻译的抑制对于减数分裂I染色体分离至关重要。因此，了解如何控制CLB3翻译以及CLB3如何抑制减数分裂我对于了解如何建立减数分裂I染色体分离模式至关重要。在特定目标3中，我们将确定CLB3如何抑制减数分裂I染色体分离。由于基本的细胞分裂机械从酵母到人都高度保守，并且鉴于该提案中描述的大多数因素也已被证明可以控制哺乳动物中的减数分裂，因此控制减数分裂的过程也可能是整个物种的保存。因此，与许多其他细胞周期研究一样，在酵母中发现和表征的调节过程可能会指导在包括人类在内的更高真核生物研究中。公共卫生相关性：减数分裂过程中产生的非整倍性是人类智力低下和流产的主要原因。因此，确定控制减数分裂染色体隔离的分子机制和确保配子形成的监视途径的准确性对于理解染色体错误分离的原理至关重要，从而导致唐氏综合症和不育。我们研究的长期目标是定义在分子水平控制减数分裂染色体分离和配子形成的机制。