Ovarian reserve formation and maintenance

卵巢储备的形成和维持

• 批准号: 10605824
• 负责人: Satoshi Namekawa
• 金额: $ 23.94万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605824
• 关键词: Adolescent; Adult; Age; Age Months; CHD4 gene; Chromatin; Chromatin Structure; Complement; Complex; Couples; DNA Methylation; Data; Data Set; Deacetylase; Deterioration; Diagnosis; Embryo; Enhancers; Epigenetic Process; Female; Female infertility; Fertility; Foundations; Functional disorder; Gene Expression; Gene Silencing; Goals; Growth; Human; Investigation; Life; Longevity; Maintenance; Mediating; Meiosis; Meiotic Prophase I; Menopause; Molecular; Molecular Analysis; Mus; Nucleosomes; Oocytes; Oogenesis; Ovarian; Ovarian aging; Ovary; PRC1 Protein; Perinatal; Phase; Polycomb; Premature Ovarian Failure; Primordial Follicle; Process; Protocols documentation; Puberty; Public Health; Research; Role; Testing; Woman; age effect; aged; data resource; design; epigenome; epigenomics; exhaustion; gene regulatory network; histone modification; human female; human old age (65+); insight; member; middle age; ovarian reserve; postnatal; programs; promoter; reproductive; reproductive senescence; single-cell RNA sequencing; sound

ABSTRACT The goal of this study is to understand how epigenetic states in oocytes that reside in primordial follicles contribute to maintenance of the ovarian reserve in women. The ovarian reserve defines female reproductive lifespan, which in humans spans decades due to maintenance of meiotic arrest in oocytes residing in primordial follicles. The quality and quantity of oocytes are critical determinants for ovarian functions, and exhaustion of primordial follicles triggers menopause. However, our understanding how the ovarian reserve is generated and maintained is currently limited due to the inability to perform molecular analysis. In our unpublished study, we developed a protocol to isolate the pool of non-growing oocytes that enabled molecular analyses. We found that the Polycomb Repressive Complex 1 establishes repressive chromatin states in perinatal mouse oocytes that directly suppress the gene expression program of meiotic prophase-I and thereby enable the transition to dictyate arrest. Based on these findings, we propose that the chromatin state is established during perinatal oogenesis that enables ovarian reserve formation and then maintained in adult and aged ovaries. In Aim 1, we will perform a comprehensive chromatin profiling of the initial pools of non- growing oocytes from juvenile ovaries and the ovarian reserve maintained in adulthood. Aim 1 will establish an epigenome data resource of the ovarian reserve. In Aim2, we designed a candidate-based approach to define the regulatory mechanism of chromatin states in the ovarian reserve. We will determine the function of CHD4, a chromatin remodeler, in maintaining the ovarian reserve. Aim 2 will provide the foundation to investigate the chromatin-based maintenance mechanisms of the ovarian reserve. The proposed research will significantly advance the field by providing molecular insights how the epigenome of the ovarian reserve is established and maintained.

抽象的 这项研究的目的是了解原始卵泡中卵母细胞的表观遗传状态如何 有助于维持女性卵巢储备功能。卵巢储备功能决定女性生殖能力 人类的寿命长达数十年，这是由于卵母细胞减数分裂的维持 原始卵泡。卵母细胞的质量和数量是卵巢功能的关键决定因素， 原始卵泡耗尽会引发更年期。然而，我们对卵巢储备功能的了解 由于无法进行分子分析，生成和维护目前受到限制。在我们的 在未发表的研究中，我们开发了一种协议来分离非生长卵母细胞池，从而使分子 分析。我们发现 Polycomb 抑制复合物 1 在 围产期小鼠卵母细胞直接抑制减数分裂前期 I 的基因表达程序，从而 实现向专断逮捕的过渡。基于这些发现，我们提出染色质状态是 在围产期卵子发生过程中建立，使卵巢储备形成并在成年后维持 和老化的卵巢。在目标 1 中，我们将对初始非染色质池进行全面的染色质分析。 来自幼年卵巢的卵母细胞的生长和成年期维持的卵巢储备。目标 1 将建立一个 卵巢储备的表观基因组数据资源。在 Aim2 中，我们设计了一种基于候选的方法来定义 卵巢储备中染色质状态的调节机制。我们将确定CHD4的功能， 染色质重塑剂，维持卵巢储备。目标 2 将为调查提供基础 基于染色质的卵巢储备维持机制。拟议的研究将显着 通过提供分子见解来推进该领域的发展，卵巢储备的表观基因组是如何建立的， 维持。