Ovarian-specific transcription networks regulated by the TFIID subunit TAF4b

TFIID 亚基 TAF4b 调控的卵巢特异性转录网络

• 批准号: 7899556
• 负责人: Richard Neil Freiman
• 金额: $ 33.72万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899556
• 关键词: Accounting; Address; Adolescent; Adult; Affect; Age; Aging; Aneuploidy; Apoptosis; Autophagocytosis; Bioinformatics; Biological; Biology; Birth; Cell Death; Chromosome Pairing; Chromosome Segregation; Chromosomes; Complex; Data; Defect; Deterioration; Development; Diagnostic; Disease; Endocrine; Estrous Cycle; Estrus; Etiology; Event; Exhibits; Female; Female infertility; Fertility; Future Generations; Gene Expression; Gene Family; Gene Targeting; General Transcription Factors; Genes; Genetic Transcription; Genomics; Germ Cells; Goals; Human; Incidence; Infertility; Knockout Mice; Knowledge; Lead; Left; Life; Link; Longevity; Maintenance; Measures; Mediating; Meiosis; Molecular; Mus; Nature; Neonatal; Oocytes; Ovarian; Ovary; Pathology; Perinatal; Periodicity; Physiological; Population; Premature Ovarian Failure; Primordial Follicle; Process; Quality Control; Recruitment Activity; Regulation; Reproductive Health; Research; Single Nucleotide Polymorphism; Sister Chromatid; Site; Symptoms; TATA-Binding Protein Associated Factors; Testing; Therapeutic; Transgenic Organisms; Turner' s Syndrome; Woman; Work; base; cohesion; emerging adult; exhaust; experience; genome wide association study; human TAF1 protein; male; mouse model; neonate; postnatal; premature; promoter; public health relevance; reproductive; reproductive function; segregation; senescence; stem; theories; tool

DESCRIPTION (provided by applicant): The mammalian ovary is unique in that its reproductive lifespan is limited by oocyte quantity and quality. Oocytes are recruited from a finite pool of primordial follicles that are usually exhausted from the ovary during mid-adult life. If regulation of this pool is perturbed, the reproductive capacity of the ovary is compromised. Previous characterization of TAF4b-deficient mouse ovaries revealed several reproductive deficits that collectively result in female infertility. By assessing estrous cyclicity, ovarian pathology and gene expression changes in young TAF4b-deficient female mice, we have determined that TAF4b-null females exhibit premature reproductive senescence. Based on these preliminary data, we hypothesize that TAF4b regulates the transcription of oocyte-specific genes required for proper maintenance of the primordial follicle pool and oocyte quality that is required for healthy fertility in the adult. The objective of the proposed research is to decipher fundamental cellular and molecular mechanisms of TAF4b in the regulation of proper primordial follicle survival and ovarian aging. To accomplish our goals we propose three related, but non-overlapping specific aims to: 1) determine the cellular mechanisms of excessive neonatal TAF4b-deficient primordial follicle attrition; 2) elucidate the TAF4b regulation of chromosome synapsis, segregation and meiosis; and 3) determine the mechanistic basis of TAF4b-dependent regulation of oocyte quality. Since TAF4b is required for normal regulation of primordial follicle development in the mouse, deregulation of TAF4b-mediated events in human ovaries may be an underlying cause of a number of female fertility defects including unexplained infertility, which accounts for 10% of female infertility, and premature ovarian failure, which is observed in 1% of the female population worldwide. In fact, recent studies of human fertility have implicated the sequence of the human TAF4b gene and its proper expression as being critical for promoting healthy oocyte quality and ovarian aging in women. Thus, elucidating the critical cellular and molecular mechanisms of TAF4b in postnatal oocyte developmental will both identify fundamental biological principles of mammalian ovarian biology as well as illuminate the etiology of female reproductive health disorders in women such as primary ovarian insufficiency. These studies will increase our basic knowledge which may allow us to preserve and/or enhance oocyte quality in women of future generations. PUBLIC HEALTH RELEVANCE: Primary ovarian insufficiency (POI), also referred to as premature ovarian failure, affects approximately 1% of women worldwide. Our preliminary data implicate TAF4b-regulated processes in the expression of critical genes in the ovary that are required for the maintenance of the primordial follicle pool and healthy ovarian aging. As recent studies of human fertility have independently linked TAF4b functions to proper ovarian aging and oocyte quality, the work proposed here to uncover the mechanisms of TAF4b in regulating ovarian aging will reveal fundamental biological principles underlying reproductive functions in women that are required for healthy fertility. These studies may lead to advanced diagnostic and therapeutic tools to better address and manage female infertility.

描述（申请人提供）：哺乳动物卵巢的独特之处在于其生殖寿命受到卵母细胞数量和质量的限制。卵母细胞是从有限的原始卵泡池中募集的，这些卵泡通常在中年时期从卵巢中耗尽。如果这个池的调节受到干扰，卵巢的生殖能力就会受到损害。TAF 4 b缺陷小鼠卵巢的先前表征揭示了共同导致雌性不育的几种生殖缺陷。通过评估年轻TAF 4 b缺陷雌性小鼠的发情周期、卵巢病理学和基因表达变化，我们确定TAF 4 b缺陷雌性小鼠表现出过早的生殖衰老。基于这些初步数据，我们假设TAF 4 b调节卵母细胞特异性基因的转录，这些基因是适当维持原始卵泡池和卵母细胞质量所必需的，而卵母细胞质量是成年人健康生育所必需的。这项研究的目的是解释TAF 4 b在调节原始卵泡存活和卵巢衰老中的基本细胞和分子机制。为了实现我们的目标，我们提出了三个相关但不重叠的具体目标：1）确定过度新生TAF 4 b缺陷的原始卵泡磨损的细胞机制; 2）阐明TAF 4 b对染色体联会、分离和减数分裂的调节; 3）确定TAF 4 b依赖性调节卵母细胞质量的机制基础。由于TAF 4 b是正常调节小鼠原始卵泡发育所必需的，因此人类卵巢中TAF 4 b介导的事件的失调可能是许多女性生育缺陷的根本原因，包括不明原因的不孕症（占女性不孕症的10%）和卵巢早衰（在全球1%的女性人口中观察到）。事实上，最近对人类生育能力的研究表明，人类TAF 4 b基因的序列及其正确表达对于促进女性健康的卵母细胞质量和卵巢衰老至关重要。因此，阐明TAF 4 b在出生后卵母细胞发育中的关键细胞和分子机制将既确定哺乳动物卵巢生物学的基本生物学原理，又阐明女性生殖健康疾病如原发性卵巢功能不全的病因。这些研究将增加我们的基础知识，使我们能够保护和/或提高后代妇女的卵母细胞质量。 公共卫生相关性：原发性卵巢功能不全（POI），也称为卵巢早衰，影响全球约1%的女性。我们的初步数据表明，TAF 4 b调控卵巢中关键基因的表达过程，这些基因是维持原始卵泡池和健康卵巢衰老所必需的。由于最近对人类生育能力的研究已经将TAF 4 b功能与适当的卵巢衰老和卵母细胞质量独立地联系起来，因此本文提出的揭示TAF 4 b调节卵巢衰老的机制的工作将揭示健康生育所需的女性生殖功能的基本生物学原理。这些研究可能会导致先进的诊断和治疗工具，以更好地解决和管理女性不孕症。