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: 10231388
• 负责人: KIMBERLY M ABT
• 金额: $ 4.6万
• 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/10231388
• 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; Regulator Genes; 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; 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.

原发性卵巢功能不全 (POI) 是美国女性常见的健康问题，其特点是过早绝经，导致 1% 的女性不孕，但大多数情况下无法确定不孕的原因。经常在成年后被诊断出来，这种情况可能是由于胚胎发育过程中卵巢储备建立不良所致。卵巢储备由原始卵泡组成。包含由一层前颗粒细胞包围的单个卵母细胞和早期卵子发生是原始卵泡发育成功或失败的两个关键因素，但对雌性种系中这些早期过程的转录控制知之甚少。我的研究重点是 TBP 相关因子 4b (TAF4b)，它是一般转录机制中性腺丰富的亚基，对于缺乏生育能力的雌性小鼠至关重要。 TAF4b 显示 POI 的多个方面，并在减数分裂和卵子发生中表现出严重缺陷。小鼠中 Taf4b 缺陷的影响可以追溯到减数分裂起始，但 TAF4b 在此过程中的功能仍然难以捉摸。为了全面了解 TAF4b 如何促进基因调控网络驱动减数分裂基因的表达并成功建立卵巢储备，Aim 1 将使用强大的早期体外系统。目的 2 将使用体内方法来评估 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。一般转录机制的组成部分调节基因表达，这对于减数分裂和卵子发生的正常进展至关重要，因此它将极大地促进该领域对女性生殖细胞发育的理解。通过参加伍兹霍尔的生殖前沿课程、在国内和国际会议上发表演讲以及赞助商的周到指导，我的培训经验将得到丰富。此外，这项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项目中进行。完成这项奖学金将推动发育生物学领域的发展，并为我提供所需的特殊准备。我实现了领导一个专注于生殖生物学的独立学术研究实验室的职业目标。