PHYSIOLOGICAL REGULATION OF GONADOTROPIN GENE EXPRESSION

促性腺激素基因表达的生理调节

• 批准号: 2196818
• 负责人: John C Marshall
• 金额: $ 16.57万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2196818
• 关键词: estradiol; estrus; experimental brain lesion; female; follicle stimulating hormone; gene expression; genetic transcription; gonadotropin releasing factor; hormone binding protein; hormone regulation /control mechanism; inhibin; laboratory rat; luteinizing hormone; male; male castration; messenger RNA; neuropeptides; ovariectomy; peptide hormone biosynthesis; posttranscriptional RNA processing; progesterone; secretion; sex hormones; testosterone

The aim of this proposal is to elucidate the roles of the pattern of the gonadotropin-releasing hormone (GnRH) pulse signal and the ambient ovarian hormonal milieu, in regulating expression of the 3 gonadotropin subunit genes in female rats. We also plan to explore a possible mechanism of steroidal regulation of subunit gene transcription, namely regulation of the duration of transcription. Reproduction in mammals is controlled by the pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH consist of a common alpha subunit and specific beta subunits, which in turn are coded by 3 genes in the gonadotrope cell. Only a single hypothalamic GnRH is known to regulate subunit gene expression and hormone secretion, though differential regulation of LH and FSH synthesis and secretion is known to occur in normal physiology. Thus differential synthesis and secretion appear to be regulated by different patterns (amplitude and frequency) of GnRH pulsatile secretion, together with the direct feedback effects of gonadal steroids and peptides on the pituitary gonadotrope cell. We propose to validate a GnRH deficient female rat model; assess effects of different patterns of exogenous GnRH pulses on subunit mRNA expression; establish if other neuropeptides are required to rapidly increase LH beta mRNA; and determine if responses are modulated by estradiol (E2), progesterone (P), inhibin, and follistatin; investigate the physiologic mechanisms regulating gene expression during the rat estrous cycle. The second goal is to test our hypothesis that the duration of increased subunit gene transcription in response to pulsatile Gn RH signals is regulated by gonadal steroid hormones. We have preliminary evidence that in response to Gn RH pulses, transcription occurs for a shorter duration in the presence of steroids and we will evaluate the roles of gonadal steroids in this respect. If proven to be true, this would be a novel mechanism of steroid regulation of gonadotropin synthesis and secretion. The critical importance of pulsatile GnRH stimulus to initiate subunit gene transcription and to maintain hormonal secretion is well documented. The pattern of GnRH pulses is known to change during ovulatory cycles and abnormalities of the mechanisms regulating GnRH frequency and amplitude appear to be an important part of syndromes causing anovulation in women. GnRH pulses are slow in hypothalamic amenorrhea (HA) and hyperprolactinemia and occur at fast frequency in polycystic ovarian disease (PCO). Our prior data in rats showed that slow frequency GnRH stimuli favor FSH beta mRNA expression and FSH secretion (as seen in HA and hyperprolactinemia), and fast frequency GnRH pulses favor alpha and LH beta mRNA expression and LH secretion (as occurs in PCO). This provides strong support to our contention that the proposed studies of the mechanisms of GnRH action in regulating gene expression in rats will allow insight into normal physiologic mechanisms, and ultimately improved methods of treating human infertility due to anovulation.

该提议的目的是阐明模式的作用 促性腺激素释放激素（GNRH）脉冲信号和环境 卵巢激素环境，调节3种促性腺激素的表达 雌性大鼠的亚基基因。 我们还计划探索可能 亚基基因转录的类固醇调节机制，即 调节转录持续时间。 哺乳动物的繁殖受到垂体激素的控制， 黄体生成激素（LH）和卵泡刺激激素（FSH）。 LH和 FSH由一个常见的α亚基和特定的β亚基组成，该亚基 反过来，促性腺细胞中的3个基因编码。 只有一个 已知下丘脑GNRH调节亚基基因表达和 激素分泌，尽管LH和FSH合成的差异调节 并且已知分泌发生在正常生理学中。 因此差异 合成和分泌似乎受不同模式调节 GnRH脉冲分泌的（振幅和频率）与 性腺类固醇和肽对垂体的直接反馈作用 性腺细胞。 我们建议验证GNRH缺乏的雌性大鼠 模型;评估不同模式的外源GNRH脉冲对 亚基mRNA表达；确定是否需要其他神经肽 快速增加LH Beta mRNA；并确定响应是否是 由雌二醇（E2），孕酮（P），抑制素和卵泡素调节； 研究调节基因表达期间基因表达的生理机制 大鼠发情循环。 第二个目标是检验我们的假设 亚基基因转录增加的持续时间 脉冲GN RH信号受性腺类固醇激素调节。 我们 有初步的证据表明，针对GN RH脉冲，转录 在类固醇存在的情况下发生较短的持续时间，我们将 在这方面评估性腺类固醇的作用。 如果被证明是 没错，这将是类固醇调节的新型机制 促性腺激素合成和分泌。 脉冲GnRH刺激启动亚基的至关重要性 基因转录和维持激素分泌有充分的文献证明。 已知GnRH脉冲的模式在排卵周期和 调节GNRH频率和振幅的机制异常 似乎是综合症引起女性发卵的重要组成部分。 下丘脑闭经（HA）和 多囊卵巢中的高泌乳素血症并以快速频率发生 疾病（PCO）。 我们在大鼠中的先前数据表明频率缓慢gnRH 刺激有利于FSHβmRNA表达和FSH分泌（如HA所示 和过度乳酸激素血症），快速频率GnRH脉冲有利于α和 LHβmRNA表达和LH分泌（如PCO中发生）。 这 为我们的论点提供了强有力的支持，即提议的研究 GnRH作用在调节大鼠基因表达中的机制将 允许深入了解正常的生理机制，并最终改善 治疗由于缺乏引起的人类不育症的方法。