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

7.项目总结/摘要 动物的繁殖需要精子和卵子的产生，精子和卵子经过受精， 通过胚胎发生的有机体。为了完成这一壮举，细胞分裂机器必须经历一个 一系列戏剧性的变化来适应这些发展的转变。人类卵母细胞产生 胚胎和减数分裂前期的逮捕，在那里他们将保持长达几十年，直到激素 刺激触发它们的生长和细胞周期的重新进入。在经历了这种长时间的停滞后，卵母细胞必须 在减数分裂中准确分离染色体，受精，然后高保真地分裂。很好- 我们认识到，人类卵母细胞失去了他们的能力，减数分裂，受精和发展的长度， 这种停滞和母亲年龄的增加，导致非整倍性的发生率显著增加， 流产和发育障碍。因此，卵母细胞通过前期停滞持续存在的能力是 对人类生命周期至关重要，但这是一个具有挑战性的研究状态，我们知道相对而言， 很少有人知道它是如何被分子调控的。 这项建议的目标是确定维持卵母细胞能力的分子程序， 在长期停滞期间分裂，以及这种状态如何受到卵巢环境的影响。面临的一个挑战 解决这一问题的方法是哺乳动物卵母细胞的有限可用性， 体内的细胞。为了应对这一挑战，我开发了扩展体外培养的策略， 来自海洋星星Patiria miniata的卵母细胞的生化量，Patiria miniata是一种强大的模式生物，其卵母细胞 与人类具有共同的特征和保守的分子机制。利用这一优势，我将 进行一系列细胞生物学和高通量分析，以询问转录，翻译， 和翻译后机制，卵母细胞制定，以加强和坚持通过其延长逮捕。 这种方法将为理解人类生育的重要方面打开新的大门， 作为一名致力于发育和生育研究的研究者，过渡到独立。

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.