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 In our unpublished study, we developed a protocol to isolate the pool of non-growing oocytes that enabled molecular analyses.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的卵母细胞中的表观遗传状态如何 有助于维持妇女的卵巢储备。卵巢储备定义女性生殖 寿命，在人类跨越数十年中，由于居住在卵母细胞中的减数分裂逮捕而导致的寿命 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，并且 原始卵泡的精疲力尽会触发更年期。但是，我们了解卵巢储备的方式 由于无法执行分子分析，目前生成和维护的限制。在我们的 未发表的研究，我们开发了一项方案，用于隔离启用分子的非生长卵母细胞的池 分析。我们发现Polycomb抑制剂1在 围产期小鼠卵母细胞直接抑制减数分裂预言的基因表达程序，从而 使过渡得出逮捕。基于这些发现，我们建议染色质状态是 在围产期卵子发生期间建立，以实现卵巢储备形成，然后在成人中维持 和老年卵巢。在AIM 1中，我们将对非 - 的初始池进行全面的染色质分析 少年卵巢和成年卵巢储备的卵母细胞的种植者生长。 AIM 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， 染色质改造，维持卵巢储备。 AIM 2将为调查 基于染色质的维护机制。拟议的研究将大大 通过提供分子见解来推进该领域 维护。