Fertility and TAF4b: Transcriptional Regulation of Murine Ovarian Reserve Establishment

生育力和 TAF4b：小鼠卵巢储备建立的转录调控

• 批准号: 10383144
• 负责人: KIMBERLY M ABT
• 金额: $ 4.68万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383144
• 关键词: 4 year old; Achievement; Address; Adoption; Adult; Affect; Age-Years; Automobile Driving; Back; Binding; Biochemistry; CRISPR/Cas technology; Cells; Cellular biology; Clinical; Complex; Critical Pathways; Data; Defect; Development; Developmental Biology; Diagnosis; Disease; Embryo; Embryonic Development; Endocrine; Etiology; Exhibits; Failure; Fellowship; Female; Female infertility; Fertility; Foundations; Gametogenesis; Gene Expression; Genes; Genetic Transcription; Germ Cells; Goals; Gonadal structure; Health; Homeobox; Human; Immunofluorescence Immunologic; In Vitro; Infertility; International; Knock-out; Knowledge; Laboratories; Laboratory Research; Lead; Life; Longevity; Meiosis; Meiotic Prophase I; Menopause; Mentors; Modeling; Molecular; Molecular Biology; Mus; Newborn Infant; Oocytes; Oogenesis; Oogonia; Ovary; Play; Population; Premature Menopause; Preparation; Primordial Follicle; Process; Reproduction; Reproductive Biology; Reproductive Health; Research; Role; Structure of primordial sex cell; System; TAF1 gene; TAF4B gene; TATA-Binding Protein Associated Factors; Testing; Training; Transcription Coactivator; Transcription Factor TFIID; Transcriptional Regulation; Tretinoin; United States; Universities; Wood material; Work; career; diminished ovarian reserve; embryonic stem cell; experience; experimental study; female fertility; fetal; frontier; gene regulatory network; granulosa cell; human female; improved; in vivo; insight; mortality; mortality risk; ovarian reserve; premature; primary ovarian insufficiency; programs; promoter; reproductive; skills; stem; stem cell differentiation; success; symposium; transcription factor

Female infertility is a common health concern in the United States. Primary ovarian insufficiency (POI) is characterized by premature menopause and it leads to infertility in 1% of the female population, but the cause of infertility cannot be determined in most cases. Although POI is often diagnosed in adult life, this condition likely stems from poor establishment of the ovarian reserve during embryonic development. The ovarian reserve is composed of primordial follicles, each of which contain a single oocyte surrounded by a layer of pre-granulosa cells. Meiosis and early oogenesis are two key contributors to the success or failure of primordial follicle development, but the transcriptional controls regulating these early processes in the female germline are poorly understood. The focus of my research is TBP-Associated factor 4b (TAF4b), which is a gonadally-enriched subunit of the general transcription machinery and it is essential for female fertility. Female mice lacking TAF4b display multiple aspects of POI and exhibit critical defects in meiosis and oogenesis. The effects of Taf4b- deficiency in the mouse can be traced back to meiotic initiation, but the function of TAF4b during this process has remained elusive. The goal of this proposal is to develop a comprehensive understanding of how TAF4b contributes to the gene regulatory network that drives expression of meiotic genes and successful establishment of the ovarian reserve. Aim 1 will use a powerful in vitro system of early oocyte development to elucidate the precise role of TAF4b in meiotic initiation and adoption of the oogenic fate. Aim 2 will use an in vivo approach to evaluate how and when TAF4b interacts with other factors that regulate meiosis and oogenesis. Ultimately, this proposal will clarify how components of the general transcription machinery regulate gene expression that is essential for proper progression of meiosis and oogenesis, and thus it will significantly contribute to the field’s understanding of female germ cell development. While completing these aims, I will develop a repertoire of skills and the key foundational knowledge required for a successful career in reproductive biology research. My training experience will be enriched by attending the Frontiers in Reproduction course in Woods Hole, presenting at national and international conferences, and thoughtful mentoring by my sponsor. Moreover, completion of this proposal will take place in the outstandingly supportive Molecular Biology, Cell Biology, and Biochemistry Graduate Program at Brown University. Completion of this fellowship will move the developmental biology field forward and provide me with the exceptional preparation required for the achievement of my career goal to lead an independent academic research laboratory focused on reproductive biology.

女性不孕症是美国普遍的健康问题。原发性卵巢不足（POI）的特征是更年期过早，这导致1％的女性人口不孕，但在大多数情况下不能确定不育的原因。尽管经常在成人生活中被诊断出POI，但这种情况可能是从胚胎开发期间卵巢储备的建立不良的步伐。卵巢储备由原始卵泡组成，每个卵泡都包含一个由颗粒前细胞层围绕的单个卵母细胞。减数分裂和早期的卵子发生是原始叶出发的成功或失败的两个关键因素，但是对女性种系中这些早期过程的转录控制却鲜为人知。我研究的重点是与TBP相关的因子4B（TAF4B），它是一般转录机制的富含性富集的亚基，对于女性生育至关重要。缺乏TAF4B的雌性小鼠在减数分裂和卵子发生中显示了POI的多个方面和暴露的临界缺陷。 TAF4B缺陷在小鼠中的影响可以追溯到减数分裂的起始，但是在此过程中TAF4B的功能仍然难以捉摸。该提案的目的是对TAF4B如何促进减数分裂基因表达和AIM 1的基因调节网络有一个全面的理解，将使用强大的早期卵母细胞开发体外体系来阐明TAF4B在减数分裂启动和卵子污染中的精确作用。 AIM 2将使用一种体内方法来评估TAF4B如何以及何时与调节减数分裂和卵子发生的其他因素相互作用。最终，该建议将阐明一般转录机制的组成部分如何调节基因表达，这对于对减数分裂和卵子发生的适当进展至关重要，因此它将显着有助于该领域对女性生殖细胞发育的理解。在完成这些目标的同时，我将开发一项技能的曲目和成功生殖生物学研究所需的重要基础知识。我的培训经验将通过参加伍兹霍尔（Woods Hole）的繁殖课程，在国家和国际会议上展示以及周到的心态来丰富我的培训经验。由我的赞助商。此外，该提案的完成将在布朗大学的分子生物学，细胞生物学和生物化学研究生课程中进行。该奖学金的完成将推动发展生物学领域的发展，并为我提供实现职业目标所需的出色准备，以领导专注于复制生物学的独立学术研究实验室。