Mechanisms Controlling Divergent Fates of Ovarian Follicles and Fertility

控制卵巢卵泡和生育力不同命运的机制

• 批准号: 9273274
• 负责人: JoAnne Stewart Richards
• 金额: $ 38.56万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273274
• 关键词: Activins; Address; Apoptosis; Attenuated; BMP2 gene; Biochemical; Biology; Caenorhabditis elegans; Cell Death; Cell Survival; Cell physiology; Cells; Contraceptive Agents; Defect; Development; Endocrine; Exhibits; FOXO1A gene; FOXO3A gene; Family; Feedback; Female; Fertility; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Impairment; Infertility; Knockout Mice; Lead; Link; Mediating; Metabolic; Modeling; Molecular; Molecular Profiling; Mus; Mutant Strains Mice; Mutation; Oocytes; Ovarian; Ovarian Follicle; Ovary; Pathway interactions; Phenotype; Physiological; Pituitary Gland; Premature Ovarian Failure; Procedures; Production; Research; Role; Serum; Signal Pathway; Signal Transduction; Somatic Cell; Steroids; Stress; Testing; Woman; base; contraceptive target; granulosa cell; improved; inhibin; man; mutant; novel; offspring; oocyte maturation; paracrine; public health relevance; reproductive; reproductive success; response; success; transcription factor

DESCRIPTION (provided by applicant): The goal of the proposed research is to determine the mechanisms by which the FOXO boxO transcription factors, FSH and ovarian---derived growth factors (activin and BMP2) regulate ovarian follicular growth and apoptosis and hence fertility. By disrupting the Foxo1 and Foxo3 genes selectively in granulosa cells, we have generated mice that are infertile with a novel phenotype that is distinct from all other known mutations in granulosa cells. The infertile phenotype can be traced to: 1) Reduced follicle growth and apoptosis leading us to discover a new paradigm: that FOXO1/3 act in granulosa cells to mediate both follicle maturation and apoptosis, and that these distinct functions of FOXO1/3 are tightly linked to specific interactions with either the activin or BMP2 signaling pathways, respectively. 2) Defective oocyte development that appears to be mediated primarily by changes in metabolic/endocrine factors emanating from the mutant cumulus cells. Analyses of cumulus and oocyte functions in the mutant mice should lead us to discover specific FOXO1/3 targets that regulate of oocyte maturation and 3) Alterations in ovarian feedback to the pituitary leading to suppressed FSH that appears to be mediated by a novel ovarian---derived factor that is not inhibin. Characterizing a new Fshb suppressor(s) has far---ranging implications for developing alternative contraceptive targets. Thus, the Foxo1/3 conditional KO mice provide a unique model in which to determine the physiological, molecular and biochemical mechanisms by which these transcriptional regulators impact apoptosis, oocyte maturation and ovarian production of a novel factor(s) that suppresses pituitary Fshb expression. To analyze these functions of Foxo1/3 that control reproductive success, we propose the following Specific Aims: I) Determine how interactions between FSH, activin, BMP2 and FOXO1/3 impact granulosa cell apoptosis in intact follicles. II) Determine the changes in cumulus cell and oocyte functions in the Foxo1/3 mutant mice that impact fertility. III) Characterize the novel Fshb inhibitory factor(s that emanate from the Foxo1/3 mutant ovaries.

描述（由申请人提供）：本研究的目的是确定 FOXO boxO 转录因子、FSH 和卵巢衍生生长因子（激活素和 BMP2）调节卵巢滤泡生长和细胞凋亡进而调节生育力的机制。通过选择性地破坏颗粒细胞中的 Foxo1 和 Foxo3 基因，我们培育出了具有与颗粒细胞中所有其他已知突变不同的新表型的不育小鼠。不孕表型可以追溯到：1）卵泡生长和细胞凋亡减少，使我们发现了一个新的范例：FOXO1/3 在颗粒细胞中发挥作用，介导卵泡成熟和细胞凋亡，并且 FOXO1/3 的这些独特功能分别与激活素或 BMP2 信号通路的特定相互作用紧密相关。 2) 卵母细胞发育缺陷，似乎主要是由突变卵丘细胞产生的代谢/内分泌因素的变化介导的。对突变小鼠卵丘和卵母细胞功能的分析应该引导我们发现调节卵母细胞成熟的特定 FOXO1/3 靶标，以及 3) 卵巢对垂体反馈的改变导致 FSH 抑制，而 FSH 似乎是由一种新的卵巢衍生因子（非抑制素）介导的。表征新的 Fshb 抑制因子对于开发替代避孕目标具有深远的影响。因此，Foxo1/3 条件 KO 小鼠提供了一个独特的模型，用于确定这些转录调节因子影响细胞凋亡、卵母细胞成熟和卵巢产生抑制垂体 Fshb 表达的新因子的生理、分子和生化机制。为了分析 Foxo1/3 控制生殖成功的功能，我们提出以下具体目标：I) 确定 FSH、激活素、BMP2 和 FOXO1/3 之间的相互作用如何影响完整卵泡中的颗粒细胞凋亡。 II) 确定 Foxo1/3 突变小鼠中卵丘细胞和卵母细胞功能的变化对生育力的影响。 III) 表征源自 Foxo1/3 突变卵巢的新型 Fshb 抑制因子。