Dynamic Regulation of the Ovarian Reserve

项目摘要 全球大约12%的夫妇不孕，1%的女性患有原发性不孕症 卵巢功能不全（POI），这是由于卵巢卵泡储备减少，往往导致 过早绝经和不孕与绝经早期相关的重要病理结果包括 骨质疏松症、心血管疾病和老年痴呆症。尽管有几个基因与女性有关， POI，约90%的病例是特发性的。通过揭示发育和分子机制 这是原始卵泡初始池的建立和成年卵巢的维持的基础。 通过在小鼠中的储备，我们将在未来更好地理解，诊断和治疗POI。我们有 发现并描述了一种名为TAF 4 b的蛋白质的作用，这种蛋白质对建立健康的 小鼠卵巢卵泡储备。TAF 4 b是一个富含性腺的转录子， TFIID因子是一种由TATA盒结合蛋白（TBP）和14个TBP组成的大型多蛋白复合物。 相关因素（TAFs）。我们研究TAF 4 b调控卵泡发育的方法， 阐明了TAF 4 b在TAF 4 b缺陷小鼠模型中的卵巢功能。总的来说，这些 研究已经揭示TAF 4 b缺陷的雌性小鼠患有POI的特征，包括持续的 发情期，血清促卵泡激素（FSH）升高，卵巢储备耗竭加速。在 除了我们自己的工作之外，一些额外的研究已经将人TAF 4 b的潜在功能与 女性生育的调节。引人注目的是，小鼠中由TAF 4 b调控的一些遗传网络 卵巢在人胎儿卵巢发育过程中似乎是保守的。总之，这些数据表明， 在人类POI和女性不孕症的背景下TAF 4 b调节过程的潜在失调。基于 根据我们以前的研究，我们假设在发育中不同的TAF 4 b调控的转录事件， 哺乳动物卵巢用于适当地维持正常的卵巢老化和生育能力。通过揭开卵母细胞- 在这些研究中，我们的目标是鉴定新的基因， 表达机制到位，以确保在妇女中成功生产高质量的卵母细胞， 也许有一天能更好地诊断和/或管理POI和其他相关的人类卵巢功能缺陷患者。 健康

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.