Molecular control of oocyte arrest, meiosis, and the transition to development

卵母细胞停滞、减数分裂和发育过渡的分子控制

• 批准号: 10679349
• 负责人: Steven Zachary Swartz
• 金额: $ 24.9万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679349
• 关键词: Address; Adult; Age; Aging; Aneuploidy; Animal Model; Animals; Biochemical; Biological; Biological Models; Cell Cycle; Cell Differentiation process; Cell division; Cells; Cellular biology; Chromosome Segregation; Chromosomes; Communication; Communities; Competence; Complex; Coupled; Cues; Development; Developmental Biology; Disease; Embryo; Embryonic Development; Ensure; Environment; Equation; Female; Fertility; Fertilization; Fibrinogen; Future; Gene Expression Profile; Genes; Genetic Transcription; Genome; Goals; Growth; Hormonal; Human; Human Development; In Vitro; Incidence; Institutes; Kinetochores; Knock-out; Length; Life Cycle Stages; Maintenance; Mass Spectrum Analysis; Maternal Age; Meiosis; Meiotic Prophase I; Mentors; Messenger RNA; Methods; Mitotic; Mitotic Spindle Apparatus; Modification; Molecular; Multiplexed Analysis of Projections by Sequencing; Oocytes; Organism; Ovarian; Ovary; Ovulation; Patiria miniata; Phase; Physiological; Ploidies; Post-Translational Protein Processing; Process; Production; Prophase; Proteome; Regulatory Element; Reproduction; Research; Research Personnel; Series; Signal Transduction; Somatic Cell; Spontaneous abortion; Starfish; Stimulus; Supporting Cell; System; Techniques; Testing; Time; Training; Transcript; Translating; Vertebrates; developmental disease; egg; high throughput analysis; human tissue; knock-down; male; metabolomics; molecular array; mutant; programs; protein metabolite; recruit; ribosome profiling; sperm cell; tissue culture

7. Project Summary / Abstract Animal reproduction requires the production of sperm and eggs which undergo fertilization to construct a new organism through embryogenesis. To accomplish this feat, the cell division machinery must undergo a dramatic series of modifications to adapt to these developmental transitions. Human oocytes arise embryonically and arrest in meiotic prophase, where they will remain for as long as decades until a hormonal stimulus triggers their growth and cell cycle re-entry. After enduring this extended arrest, oocytes must accurately segregate chromosomes in meiosis, be fertilized, and then divide with high fidelity. It is well- appreciated that human oocytes lose their competency for meiosis, fertilization, and development as the length of this arrest and the maternal age increases, resulting in markedly increased incidence of aneuploidies, miscarriage and development disorders. The ability of an oocyte to persist through prophase arrest is therefore of paramount importance for the human life cycle, but is a challenging state to study, and we know relatively little about how it is molecularly regulated. The goal of this proposal is to define the molecular program that maintains oocyte competency for future division during extended arrest, and how this state is influenced by the ovarian environment. A challenge for addressing this question has been the limited availability of mammalian oocytes, which are among the rarest cells in the body. To address this challenge, I have developed strategies for extended in vitro culture of biochemical quantities of oocytes from the sea star Patiria miniata, a powerful model organism whose oocytes share common features and conserved molecular mechanisms with humans. Leveraging this advantage, I will perform a series of cell biological and high-throughput analyses to interrogate the transcriptional, translational, and post-translational mechanisms that oocytes enact to enforce and persist through their extended arrest. This approach will open new doors for understanding important aspects of human fertility, and will enable my transition to independence as an investigator committed to the study of development and fertility.

7。项目摘要 /摘要 动物繁殖需要生产精子和卵子，这些精子和卵受精以构建一种新的 通过胚胎发生的生物体。为了完成这一壮举，细胞部机械必须经历 戏剧性的修改以适应这些发展过渡。人类卵母细胞出现 胚胎和减数分裂预言中有逮捕 刺激会触发其生长和细胞周期重新进入。忍受了这一扩展逮捕后，卵母细胞必须 准确地将减数分裂中的染色体隔离，被施肥，然后以高保真度分裂。这是很好的 感谢人类卵母细胞失去了减数分裂，施肥和发育能力的能力 这种逮捕和产妇的年龄增加，导致非整倍性发生率显着增加， 流产和发展障碍。因此 对于人类生命周期至关重要，但是一个充满挑战的国家，我们知道 几乎没有分子调节它。 该提议的目的是定义具有未来卵母细胞能力的分子程序 扩展被捕期间的分裂，以及该州如何受卵巢环境的影响。一个挑战 解决这个问题的是哺乳动物卵母细胞的有限可用性，这是最稀有的 体内细胞。为了应对这一挑战，我制定了扩展体外文化的策略 来自Sea Star Patiria Miniata的卵母细胞的生化量，这是一种强大的模型有机体，其卵母细胞的卵母细胞 与人类共享共同的特征和保守的分子机制。利用这一优势，我会 执行一系列细胞生物学和高通量分析，以询问转录，翻译， 卵母细胞制定的翻译后机制通过其扩展逮捕来执行和持续。 这种方法将为了解人类生育的重要方面打开新的大门，并将使我 过渡到独立性，作为致力于发展和生育研究的研究者。