Dynamic Regulation of the Ovarian Reserve

卵巢储备的动态调节

• 批准号: 9762132
• 负责人: Richard Neil Freiman
• 金额: $ 41.76万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762132
• 关键词: Ablation; Acceleration; Adult; Affect; Alzheimer' s Disease; Birth; CRISPR/Cas technology; Cardiovascular system; Cells; Complex; Coupled; Couples; Critical Pathways; Data; Development; Diagnosis; Embryo; Endocrine; Ensure; Epigenetic Process; Estrus; Event; FOXL2 gene; Female; Female infertility; Fertility; Follicle Stimulating Hormone; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Germ Cells; Goals; Gonadal structure; Gonadotropins; Health; Human; Infertility; Intervention; Link; Maintenance; Measures; Mediating; Meiosis; Messenger RNA; Modification; Molecular; Multiprotein Complexes; Mus; Oocytes; Oogenesis; Osteoporosis; Outcome; Ovarian; Ovarian Follicle; Ovarian aging; Ovary; Pathologic; Pathway interactions; Patients; Periodicity; Pharmacologic Substance; Play; Population; Premature Menopause; Premature Ovarian Failure; Primordial Follicle; Process; Production; Prophase; Proteins; Regulation; Regulator Genes; Role; Serum; TAF4B gene; TATA-Binding Protein Associated Factors; TATA-Box Binding Protein; Testing; Time; Transcription Factor TFIID; Transgenic Mice; Transgenic Organisms; Woman; Work; base; blastomere structure; cancer therapy; cell type; differential expression; diminished ovarian reserve; experience; female fertility; fertility preservation; fetal; folliculogenesis; granulosa cell; improved; mouse model; novel; novel diagnostics; oocyte quality; ovarian reserve; postnatal; premature; primary ovarian insufficiency; programs; reproductive; transcription factor; transcriptome sequencing; young woman

Project Summary Approximately 12% of couples are infertile and 1% of the female population worldwide experiences primary ovarian insufficiency (POI) which results from a reduction of the ovarian follicle reserve that often leads to premature menopause and infertility. Important pathological outcomes associated with early menopause include osteoporosis, cardiovascular and Alzheimer's disease. Although several genes have been linked to women with POI, about 90% of the cases are idiopathic. By uncovering the developmental and molecular mechanisms underlying the establishment of the initial pool of primordial follicles and the maintenance of the adult ovarian reserve in the mouse, we will be poised to better understand, diagnose and treat POI in the future. We have discovered and characterized the roles of a protein called TAF4b that is essential for establishing the healthy ovarian follicle reserve in the mouse ovary. TAF4b is a gonadal-enriched subunit of the general transcription factor TFIID, a large multiprotein complex composed of the TATA-box binding protein (TBP) and 14 TBP- associated factors (TAFs). Our approach to studying the regulation of ovarian follicle development by TAF4b has elucidated the ovarian functions of TAF4b in the context of a TAF4b-deficient mouse model. Collectively, these studies have revealed that TAF4b-deficient female mice suffer from hallmarks of POI including persistent estrous, elevated serum follicle stimulating hormone (FSH) and accelerated ovarian reserve depletion. In addition to our own work, a number of additional studies have linked the potential function of human TAF4b in the regulation of fertility in women. Strikingly, some of the genetic networks regulated by TAF4b in the mouse ovary appear to be conserved during human fetal ovary development. Together, these data implicate the potential deregulation of TAF4b-regulated processes in the context of human POI and female infertility. Based upon our previous studies, we hypothesize that diverse TAF4b-regulated transcriptional events in the developing mammalian ovary serve to properly maintain normal ovarian aging and fertility. By uncovering the oocyte- and granulosa cell-specific functions and mechanisms of TAF4b in these studies, we aim to identify novel genes and expression mechanisms in place to ensure the successful production of high quality oocytes in women and perhaps one day better diagnose and/or manage patients with POI and other related deficits of human ovarian health.

项目概要 全球大约 12% 的夫妇不孕不育，1% 的女性人口患有初级疾病 卵巢功能不全（POI）是由于卵巢卵泡储备减少而导致的，这通常会导致 过早绝经和不孕。与早期绝经相关的重要病理结果包括 骨质疏松症、心血管病和阿尔茨海默病。尽管有几个基因与女性有关联 POI，大约90%的病例是特发性的。通过揭示发育和分子机制 原始卵泡初始库的建立和成人卵巢的维持的基础 保留在小鼠中，我们将在未来更好地理解、诊断和治疗 POI。我们有 发现并表征了一种名为 TAF4b 的蛋白质的作用，该蛋白质对于建立健康的身体至关重要 小鼠卵巢中的卵泡储备。 TAF4b 是一般转录的性腺富集亚基 TFIID 因子，一种由 TATA-box 结合蛋白 (TBP) 和 14 TBP-组成的大型多蛋白复合物 相关因素（TAF）。我们研究 TAF4b 调节卵泡发育的方法 在 TAF4b 缺陷小鼠模型中阐明了 TAF4b 的卵巢功能。总的来说，这些 研究表明，TAF4b 缺陷的雌性小鼠患有 POI 特征，包括持续性 发情期、血清卵泡刺激素（FSH）升高和卵巢储备加速耗竭。在 除了我们自己的工作之外，许多其他研究也将人类 TAF4b 的潜在功能与 女性生育力的调节。引人注目的是，小鼠中一些受 TAF4b 调节的遗传网络 在人类胎儿卵巢发育过程中，卵巢似乎是保守的。这些数据共同表明 在人类 POI 和女性不孕的背景下，TAF4b 调控过程的潜在放松。基于 根据我们之前的研究，我们假设发育中的多种 TAF4b 调节转录事件 哺乳动物的卵巢有助于维持正常的卵巢老化和生育能力。通过揭开卵母细胞和 在这些研究中，我们旨在识别 TAF4b 的颗粒细胞特异性功能和机制，并鉴定新的基因和 适当的表达机制可确保女性和女性成功产生高质量的卵母细胞 也许有一天可以更好地诊断和/或管理患有 POI 和其他相关人类卵巢缺陷的患者 健康。