REGULATION OF OVARIAN INHIBIN AND ACTIVIN SUBUNIT GENE EXPRESSION

卵巢抑制素和激活素亚基基因表达的调控

• 批准号: 6108456
• 负责人: KELLY E MAYO
• 金额: $ 13.55万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 1999-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6108456
• 关键词: biological signal transduction; cAMP response element binding protein; cell line; cyclic AMP; estrus; female; follicle stimulating hormone; gene expression; gene induction /repression; genetic promoter element; genetic regulatory element; genetically modified animals; granulosa cell; hormone regulation /control mechanism; in situ hybridization; inhibin; laboratory mouse; laboratory rat; luteinizing hormone; polymerase chain reaction; protein isoforms; protein kinase A; protein kinase C; protein protein interaction; transcription factor

The objective of this research proposal is to understand the hormonal regulation and tissue-specific expression of the genes encoding the inhibins and activins, gonadal proteins that play key roles in the control of FSH synthesis and secretion. Inhibin (an alpha-beta dimer) has endocrine actions on pituitary FSH secretion and is a paracrine modulator of gonadal activity, while activin (a beta-beta dimer) regulates growth and differentiation in many target tissues. The inhibin and activin alpha and beta subunit mRNAs are expressed in granulosa cells of the rodent ovary and are tightly regulated by the pituitary gonadotropins, FSH and LH. FSH stimulates inhibin subunit mRNA levels in growing follicles, while LH potently down-regulates inhibin subunit mRNA levels in mature preovulatory follicles. The proposed studies will investigate the DNA promoter elements and protein important for the hormonal regulation and cell-specific expression of the alpha and beta subunit genes in ovarian granulosa cells. There are four interrelated experimental aims. The first two aims utilize molecular and genetic approaches to investigate mechanisms whereby the preovulatory LH surge suppresses inhibin gene expression. This is a physiologically important event, in that the resulting decrease in inhibin secretion provides an environment permission to the secondary surge of FSH and recruitment of a new cohort of follicles. Aim 1 will establish the role of inducible cAMP early repressor (ICER), a potent transcriptional repressor for several gonadotropin and cAMP-regulated genes, in the LH suppression of inhibin alpha subunit gene expression in preovulatory granulosa cells. Aim 2 will determine if repressor forms of CAAT/enhancer binding protein-beta (C/EBPbeta), a transcription factor that plays a critical role in ovarian function, are expressed in the ovary and involved in LH regulation of inhibin alpha subunit gene expression. The third specific aim investigates regulation of the beta/alpha subunit gene, which is common to inhibin A and activin A, in granulosa cells. Aim 3 examines the function of a novel cAMP and phorbol ester final specific aim addresses the important issue of tissue- specific expression of the inhibin alpha subunit gene in the reproductive axis. Aim 4 will investigate the role of steroidogenic factor-1 (SF-1) in tissue specific expression of the alpha subunit gene using cell transfection and transgenic animal approaches. These studies are expected to provide insight into the regulation of inhibin and activin in the reproductive system that will facilitate understanding their involvement in reproductive diseases or dysfunctions of importance to human health.

这项研究计划的目的是了解荷尔蒙 编码该基因的调控和组织特异性表达 抑制素和激活素，性腺蛋白，在控制中起关键作用 促性腺激素的合成和分泌。抑制素(一种α-β二聚体) 内分泌作用于垂体FSH分泌，是一种旁分泌调节剂 性腺活动，而激活素(一种β-β二聚体)调节生长 以及在许多靶组织中的分化。抑制素和激活素α 和β亚基mRNAs在啮齿动物的颗粒细胞中表达 卵巢，并受到垂体促性腺激素、卵泡刺激素和 左撇子。FSH刺激生长卵泡中抑制素亚单位的mRNA水平，而 促黄体生成素有效下调成熟期抑制素亚单位mRNA水平 排卵前卵泡。拟议中的研究将调查DNA 启动子元件和蛋白质对激素调节和 卵巢中α和β亚基基因的细胞特异性表达 颗粒细胞。有四个相互关联的实验目标。第一 两个目的是利用分子和遗传方法来研究 排卵前促黄体生成素高峰抑制抑制素基因的机制 表情。这是一个生理上重要的事件，因为 由此导致的抑制素分泌的减少提供了环境许可 与FSH的二次激增和招募一批新的 毛囊。目标1将确定可诱导的cAMP早期抑制因子的作用 (ICER)，几种促性腺激素和促性腺激素的有效转录抑制物 抑制素α亚单位基因抑制中的cAMP调节基因 在排卵前颗粒细胞中表达。目标2将决定是否 抑制型CAAT/增强子结合蛋白-β(C/EBPbeta)，a 在卵巢功能中起关键作用的转录因子是 抑制素α在卵巢中表达并参与黄体生成素的调节 亚单位基因表达。第三个具体目的是调查监管 抑制素A和激活素A共有的β/α亚基基因， 在颗粒细胞中。目标3研究了一个新的cAMP的功能和 佛波酯最终的具体目标是解决组织的重要问题-- 抑制素α亚基基因在生殖器官中的特异性表达 轴心。目的4研究类固醇生成因子-1(SF-1)在脑出血中的作用。 利用细胞技术实现α亚基基因的组织特异性表达 转染法和转基因动物法。这些研究是预期的 为了深入了解抑制素和激活素在体内的调节 生殖系统将有助于理解他们的参与 对人类健康具有重要意义的生殖疾病或功能障碍。