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: 8694652
• 负责人: JoAnne Stewart Richards
• 金额: $ 35.63万
• 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/8694652
• 关键词: Accounting; Activins; Address; Affect; Apoptosis; Attenuated; BMP2 gene; Biochemical; Biology; Caenorhabditis elegans; Cell Death; Cell Survival; Cell physiology; Cells; Contraceptive Agents; Defect; Development; Endocrine; Exhibits; Family; Feedback; Female; Fertility; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; Growth; Growth Factor; 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; Staging; 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）：拟议研究的目的是确定Foxo Boxo转录因子FSH和卵巢的机制 - 衍生生长因子（Activin和BMP2）调节卵巢卵泡生长和凋亡以及生育力。通过在颗粒细胞中选择性破坏FOXO1和FOXO3基因，我们产生的小鼠与颗粒细胞中所有其他已知突变不同的新表型不差。可以追溯到：1）卵泡生长和凋亡降低，导致我们发现了一种新的范式：FOXO1/3在颗粒细胞中起作用以介导卵泡的成熟和凋亡，以及FOXO1/3的这些独特功能与特定的激活或BMP2信号相互链接。 2）卵母细胞发育有缺陷，似乎主要是由突变源细胞产生的代谢/内分泌因子的变化介导的。突变小鼠中积积和卵母细胞功能的分析应导致我们发现调节卵母细胞成熟的特定FOXO1/3靶标，而3）卵巢反馈对垂体的反馈改变，导致抑制FSH，这似乎是由一种新的卵巢介导的卵巢 - 未抑制素的卵巢因子。表征新的FSHB抑制器具有远 - 对开发替代避孕目标的影响。因此，FOXO1/3条件KO小鼠提供了一个独特的模型，在该模型中，这些模型可以确定这些转录调节剂影响凋亡，卵母细胞成熟和卵巢产生的新型因素的生理，分子和生化机制，从而抑制垂体FSHB表达。为了分析控制生殖成功的FOXO1/3的这些功能，我们提出了以下特定目的：i）确定FSH，Activin，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细胞凋亡。 ii）确定影响生育能力的FOXO1/3突变小鼠中库卢斯细胞和卵母细胞功能的变化。 iii）表征了新型的FSHB抑制因子（从FOXO1/3突变卵巢发出的s。