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: 6301921
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-12-15 至 2000-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6301921
• 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激素 调控和组织特异性表达的基因编码的 性腺激素和激活素，性腺蛋白，在控制 FSH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（β-β二聚体）调节生长 和分化。激活素和激活素α 和β亚基mRNA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，FSH和 LH。FSH刺激生长卵泡中抑制素亚基mRNA水平，而 LH有效地下调成熟卵巢中的BMPin亚基mRNA水平 排卵前卵泡拟议的研究将调查DNA 启动子元件和对激素调节重要的蛋白质， 卵巢癌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 两个目标利用分子和遗传学方法来研究 排卵前LH峰抑制Escherichin基因的机制 表情这是一个重要的生理事件，因为 由此导致的大肠杆菌素分泌的减少提供了环境许可 FSH的二次激增和招募新的 毛囊目的1建立诱导型cAMP早期阻遏物的作用 （ICER），一种有效的几种促性腺激素的转录抑制因子， cAMP调节基因，在LH抑制中的α亚基基因 在排卵前颗粒细胞中表达。目标2将确定是否 CAAT/增强子结合蛋白-β（C/EBP β）的阻遏物形式， 在卵巢功能中起关键作用的转录因子， 在卵巢中表达，参与LH对BABIN α的调节 亚基基因表达第三个具体目标是调查监管 β/α亚基基因，其是腺苷酸结合素A和激活素A所共有的， 在颗粒细胞中。目的3研究一种新的cAMP的功能， 佛波醇酯最终的具体目标解决了组织的重要问题， 在生殖细胞中特异性表达α亚基基因 轴线目的4探讨类固醇生成因子-1（SF-1）在卵巢癌中的作用。 使用细胞的α亚基基因的组织特异性表达 转染和转基因动物方法。这些研究预计 为了深入了解在细胞内对Escherichin和Activin的调节， 生殖系统，这将有助于了解他们的参与 对人类健康具有重要意义的生殖疾病或功能障碍。