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 In our unpublished study, we developed a protocol to isolate the pool of non-growing oocytes that enabled molecular analyses.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.

摘要 本研究的目的是了解原始卵泡中卵母细胞的表观遗传状态 有助于维持女性的卵巢储备。卵巢储备决定了女性的生殖能力 寿命，在人类中跨越几十年，由于维持减数分裂停滞在卵母细胞居住在 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， 原始卵泡的衰竭会引发更年期。然而，我们对卵巢储备的了解 由于不能进行分子分析，目前产生和维持的DNA是有限的。在我们 在一项未发表的研究中，我们开发了一种方案来分离非生长卵母细胞池， 分析。我们发现Polycomb抑制复合物1在细胞中建立了抑制染色质状态 围产期小鼠卵母细胞直接抑制减数分裂前体蛋白酶-I的基因表达程序， 使其能够过渡到独裁逮捕。基于这些发现，我们提出染色质状态是 在围产期卵子发生期间建立，使卵巢储备形成，然后在成年期维持 卵巢老化在目标1中，我们将对非特异性DNA的初始池进行全面的染色质分析。 从青少年卵巢中生长卵母细胞，并在成年期维持卵巢储备。目标1将建立一个 卵巢储备的表观基因组数据资源。在Aim 2中，我们设计了一种基于候选人的方法来定义 卵巢储备中染色质状态的调节机制。我们将确定CHD 4的功能， 一种染色质重塑剂，维持卵巢储备。目标2将为研究 基于染色质的卵巢储备维持机制。这项研究将大大 通过提供卵巢储备表观基因组如何建立的分子见解来推进该领域， 树立政治意识