Transcriptional control of pituitary gonadotropin genes

垂体促性腺激素基因的转录控制

• 批准号: 8185182
• 负责人: Varykina G Thackray
• 金额: $ 33.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-23 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185182
• 关键词: Ablation; Activins; Address; Amenorrhea; Anterior Pituitary Gland; Apoptosis; Binding; Biochemical; Caenorhabditis elegans; Cell Nucleus; Cell model; Cell physiology; Cells; Complex; Contraceptive methods; Cues; Cytoplasm; Data; Development; Disease; Female; Fertility; Follicle Stimulating Hormone; Funding; Gametogenesis; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Gonadotrope Cell; Gonadotropins; Hormonal; Hormones; Hyperinsulinism; Hypogonadism; In Vitro; Infertility; Insulin; Knock-out; Knockout Mice; Lead; Link; Longevity; Luteinizing Hormone; Menstrual cycle; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; Mus; Nematoda; Neurosecretory Systems; Obesity; Orthologous Gene; Ovarian; Ovulation; Phenotype; Phosphorylation; Pituitary Gland; Pituitary Gonadotropins; Play; Precocious Puberty; Production; Proteins; Regulation; Reproduction; Reproductive Endocrinology; Research; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Staging; Steroid biosynthesis; Stress; Syndrome; Testing; Tissues; Transcriptional Regulation; Transgenic Mice; Woman; Work; abstracting; base; forkhead protein; hypothalamic pituitary gonadal axis; in vivo; insight; insulin signaling; male; mouse model; novel; novel strategies; overexpression; programs; reproductive; tissue culture; tissue/cell culture; transcription factor

DESCRIPTION (provided by applicant): Project Summary/Abstract Fertility depends on proper neuroendocrine regulation of the hypothalamic-pituitary-gonadal axis. Metabolic disorders, including obesity, are often characterized by hyperinsulinemia and associated with reduced fertility in women. Production of gonadotropin hormones critical for steroidogenesis, gametogenesis and ovulation is also disturbed in these disorders. The overall goal of this application is to determine whether gonadotropin gene expression is regulated by forkhead transcription factors in pituitary gonadotrope cells. FoxO proteins are regulated by insulin signaling and thus, may be an important regulatory link between metabolic status and fertility. FoxOs regulate diverse cellular functions, such as apoptosis, stress resistance and metabolism, but their role in the neuroendocrine regulation of reproduction has not been extensively explored. Our preliminary results indicate that FoxO1 is expressed in pituitary gonadotrope cells and that FoxO1 phosphorylation and cellular localization is regulated by insulin in these cells. Our preliminary studies also show that FoxO1 suppresses basal and GnRH induction of luteinizing hormone and follicle-stimulating hormone. Our hypothesis is that the FoxO1 transcription factor suppresses gonadotropin synthesis in pituitary gonadotrope cells and that insulin signaling relieves this suppression by rendering FoxO1 transcriptionally inactive. In this proposal, we will utilize novel approaches to study mechanisms of FoxO1 transcriptional regulation of gonadotropin synthesis in vitro and in vivo. In Specific Aim 1, a pituitary-specific knockout mouse model will be used to determine whether FoxO1 expression in the gonadotrope is necessary for fertility and whether FoxO1 plays a role in obesity-related infertility. In Specific Aim 2, biochemical and tissue cell culture models will be used to characterize mechanisms of FoxO1 regulation of gonadotropin production. Specific Aim 3 will address mechanisms of insulin signal transduction via FoxO1 in gonadotrope cells and determine if disruption of insulin regulation of FoxO1 impacts fertility using a conditionally active FoxO1 transgenic mouse model. Results from this proposal have the potential to answer fundamental questions regarding the role of FoxO1 in gonadotropin production and provide insight into broad mechanisms of hormonal control of fertility. Understanding these mechanisms may be relevant for the development of novel contraceptive methods or infertility treatments. Potential applications could also lead to new directions in treating a range of disorders that can result from malfunction in gonadotropin production, such as amenorrhea, precocious puberty, ideopathic hypogonadism, and polycystic ovarian syndrome. Funding of this proposal will also allow the PI, as an Early-Stage Investigator, to establish a fully-independent research program in the field of reproductive endocrinology. PUBLIC HEALTH RELEVANCE: Project Narrative This research project has particular relevance to the growing epidemic of obesity in women of child-bearing age. Obesity is associated with increased reproductive disorders including early onset of puberty, menstrual irregularities, pregnancy complications, and infertility due to anovulation, spontaneous abortions, and polycystic ovarian syndrome. Since obesity is also associated with alterations in gonadotropin hormone production, it is vital that we identify and characterize the mechanisms of gonadotropin synthesis to provide insight into the etiology of obesity-related infertility and its treatment.

描述（由申请人提供）： 项目摘要/抽象的生育能力取决于下丘脑 - 垂体 - 基达轴的适当神经内分泌调节。包括肥胖症在内的代谢疾病通常以高胰岛素血症和妇女的生育能力降低有关。在这些疾病中，对类固醇生成，配子发生和排卵至关重要的促性腺激素激素的产生也受到干扰。该应用的总体目的是确定促性腺激素基因表达是否受到垂体促性腺细胞中的叉头转录因子的调节。 FOXO蛋白质受胰岛素信号传导的调节，因此，可能是代谢状态与生育能力之间的重要调节联系。 FOXOS调节多种细胞功能，例如凋亡，抗压力和代谢，但是尚未广泛探索它们在神经内分泌调节中的作用。我们的初步结果表明，FOXO1在垂体性促性腺细胞中表达，FOXO1磷酸化和细胞定位受这些细胞中胰岛素的调节。我们的初步研究还表明，FOXO1抑制了黄体生成激素和卵泡刺激激素的基础和GNRH诱导。我们的假设是，FOXO1转录因子抑制了垂体性促性腺细胞中的促性腺激素合成，并且胰岛素信号传导通过使FOXO1在转录上无活性来缓解这种抑制。在此提案中，我们将利用新颖的方法来研究体外和体内促性腺激素合成的FOXO1转录调节的机制。在特定的目标1中，将使用垂体特异性小鼠模型来确定促性腺素中的FOXO1表达是否对于生育力是必需的，以及FOXO1是否在与肥胖相关的不育症中起作用。在特定的目标2中，将使用生化和组织细胞培养模型来表征促性腺激素产生的FOXO1调节机制。具体目标3将解决通过促性腺细胞中FOXO1通过FOXO1转导的机制，并确定使用有条件活跃的FOXO1转基因小鼠模型的FOXO1调节的破坏是否会影响生育力。该提案的结果有可能回答有关FOXO1在促性腺激素生产中的作用的基本问题，并洞悉了荷尔蒙控制生育能力的广泛机制。了解这些机制可能与开发新颖的避孕方法或不孕治疗有关。潜在的应用还可能导致新的方向，以治疗促性腺激素产生故障导致的一系列疾病，例如闭经，早产青春期，意识形态性障碍和多囊性卵巢综合征。该提案的资金还将允许作为早期研究者PI在生殖内分泌学领域建立完全独立的研究计划。 公共卫生相关性： 项目叙述这项研究项目与育龄妇女的肥胖流行病特别相关。肥胖与生殖疾病增加有关，包括青春期的早期发作，月经不规则，妊娠并发症以及由于发酵，自发流产和多囊卵巢综合征而导致的不育症。由于肥胖症也与促性腺激素激素产生的改变有关，因此我们必须识别并表征促性腺激素合成的机制至关重要，以提供对肥胖症相关性不育症及其治疗的病因及其治疗的洞察力。