Dynamic Regulation of the Ovarian Reserve

项目摘要 大约12%的夫妇不育，全球1%的女性经历了初孕 卵巢功能不全(POI)，由卵巢卵泡储备减少引起，通常导致 过早绝经和不孕不育。与早期绝经有关的重要病理结果包括 骨质疏松症、心血管疾病和阿尔茨海默病。尽管有几个基因被认为与女性 POI，大约90%的病例是特发性的。通过揭示发育和分子机制 原始卵泡池的建立和成人卵巢的维持 保留在小鼠体内，我们将为未来更好地了解、诊断和治疗POI做好准备。我们有 发现并鉴定了一种名为TAF4b的蛋白质的作用，这种蛋白质对建立健康的 小鼠卵巢中的卵泡储备。TAF4b是一般转录的性腺富集亚单位 因子TFIID是一个由TATA盒结合蛋白(TBP)和14TBP组成的大型多蛋白复合体。 相关因素(TAFs)。我们研究TAF4b对卵泡发育调控的方法有 在TAF4b缺陷小鼠模型的背景下阐明了TAF4b的卵巢功能。总而言之，这些 研究表明，缺乏TAF4b的雌性小鼠患有POI的特征，包括持续性 发情、血清卵泡刺激素(FSH)升高和卵巢储备加速枯竭。在……里面 除了我们自己的工作，一些额外的研究已经将人类TAF4b的潜在功能联系到了 对妇女生育能力的调节。值得注意的是，TAF4b在小鼠体内调控的一些遗传网络 在人类胚胎卵巢发育过程中，卵巢似乎是保守的。总而言之，这些数据表明 在人类POI和女性不孕的背景下，TAF4b调节过程的潜在解除管制。基座 根据我们以前的研究，我们假设在发育过程中不同的TAF4b调节的转录事件 哺乳动物卵巢起到适当维持卵巢正常衰老和生育的作用。通过发现卵母细胞--以及 TAF4b的颗粒细胞特异性功能和机制在这些研究中，我们的目标是识别新的基因和 建立表达机制，以确保成功生产高质量的卵子 也许有一天能更好地诊断和/或处理卵巢早搏和其他相关卵巢缺陷的患者 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.