Transcriptional control of pituitary gonadotropin genes

垂体促性腺激素基因的转录控制

• 批准号: 8322336
• 负责人: Varykina G Thackray
• 金额: $ 33.7万
• 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/8322336
• 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.

描述（由申请人提供）： 生育力取决于下丘脑-垂体-性腺轴的适当神经内分泌调节。代谢紊乱，包括肥胖症，通常以高胰岛素血症为特征，并与女性生育力下降有关。在这些疾病中，对类固醇生成、配子生成和排卵至关重要的促性腺激素的产生也受到干扰。本申请的总体目标是确定促性腺激素基因表达是否受垂体促性腺激素细胞中叉头转录因子的调控。FoxO蛋白受胰岛素信号传导调节，因此可能是代谢状态和生育力之间的重要调节环节。FoxOs调节多种细胞功能，如细胞凋亡、抗应激和代谢，但它们在生殖的神经内分泌调节中的作用尚未得到广泛研究。我们的初步结果表明，FoxO 1在垂体促性腺细胞中表达，FoxO 1磷酸化和细胞定位在这些细胞中受胰岛素调节。我们的初步研究还表明，FoxO 1抑制基础和GnRH诱导的促黄体激素和促卵泡激素。我们的假设是FoxO 1转录因子抑制垂体促性腺激素细胞的促性腺激素合成，胰岛素信号通过使FoxO 1转录失活来缓解这种抑制。在这个提议中，我们将利用新的方法来研究FoxO 1的转录调控促性腺激素合成的机制在体外和体内。在特定目标1中，将使用垂体特异性敲除小鼠模型来确定促性腺细胞中的FoxO 1表达是否是生育所必需的，以及FoxO 1是否在肥胖相关的不孕症中起作用。在具体目标2中，将使用生化和组织细胞培养模型来表征FoxO 1调节促性腺激素产生的机制。具体目标3将解决促性腺细胞中通过FoxO 1的胰岛素信号转导机制，并使用条件活性FoxO 1转基因小鼠模型确定FoxO 1的胰岛素调节中断是否影响生育能力。从这个建议的结果有可能回答有关FoxO 1在促性腺激素产生中的作用的基本问题，并提供深入了解生育激素控制的广泛机制。了解这些机制可能与开发新的避孕方法或不孕症治疗有关。潜在的应用也可能为治疗一系列由促性腺激素产生功能障碍引起的疾病开辟新的方向，如闭经、性早熟、特发性性腺功能减退和多囊卵巢综合征。该提案的资助还将允许PI作为早期研究者在生殖内分泌学领域建立完全独立的研究项目。