TRANSCRIPTION FACTOR INTERACTIONS IN REPRODUCTIVE HORMONE GENE EXPRESSION

生殖激素基因表达中转录因子的相互作用

• 批准号: 7490116
• 负责人: KELLY E MAYO
• 金额: $ 28.48万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-23 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490116
• 关键词: Ablation; Activins; Adrenal gland hypofunction; Animals; Biological Models; CREB1 gene; Cell Line; Cells; Complex; Cyclic AMP; Cyclic AMP-Responsive DNA-Binding Protein; DNA Binding Domain; Development; Disease; E1A-associated p300 protein; Estrous Cycle; FHL2 gene; Family; Female; Fertility; Follicle Stimulating Hormone; Foundations; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Gonadal Hormones; Gonadal structure; Gonadotropins; Health; Hormones; Human; Infertility; Knowledge; Lead; Luteinization; Maintenance; Malignant neoplasm of ovary; Maps; Mediating; Menstrual cycle; Molecular; Mus; Mutate; Mutation; Nuclear Receptors; Numbers; Organism; Ovarian; Ovarian Follicle; Ovary; Ovulation; Pathway interactions; Phosphorylation; Pituitary Gland; Pituitary Gonadotropins; Post-Translational Protein Processing; Premature Ovarian Failure; Protein Family; Proteins; RNA Interference; Regulation; Relative (related person); Reproductive system; Research Proposals; Rodent; Role; Signal Pathway; Site; Staging; Stromal Cells; Structure; Syndrome; Tissues; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; Tumor Suppressor Genes; base; fitness; folliculogenesis; genetic regulatory protein; granulosa cell; human disease; inhibin; novel; promoter; reproductive; reproductive hormone; reproductive success; research study; sex; structural biology; synergism; transcription factor; tumor

The actions of inhibin and activin as modulators of pituitary FSH synthesis and secretion and as local regulatory factors within the gonads makes them of key significance for maintaining reproductive fitness and suggests their involvement in reproductive dysfunction (114). Neutralization of inhibin increases follicular maturation and ovulation in animals (115, 116). Ablation of the a inhibin gene in mice results in formation of gonadal stromal cell tumors, implicating inhibin as a tumor-suppressor gene (117). Conversely, over-expression of inhibin in mice results in suppressed fertility and disrupted folliculogenesis (118). In the human, inhibin is an early marker for some types of ovarian cancer (6), is inappropriately regulated in polycystic ovarian syndrome (7) and may be mutated in some cases of premature ovarian failure (8, 9). Transcription factors regulating inhibin expression are also involved in human disease (119, 120), with perhaps the best example being SF-1 mutations in gonadal and adrenal insufficiency and XY sex-reversal (121, 122). This proposal is aimed at understanding how the inhibin gene is expressed and regulated by the pituitary gonadotropins in the ovary and in follicular granulosa cells, focusing on the structural features and interactions of the transcription factors and coactivators important for this regulation. Figure 2 outlines our current understanding of inhibin gene expression during the reproductive cycle, and points to key aspects of this regulation that we plan to further investigate. While the proposed experiments will focus on the inhibin a subunit gene, we expect these findings to be broadly applicable to understanding gonadotropinand cAMP-dependent signaling pathways regulating gene expression in the mammalian ovary. This basic knowledge is expected to provide a foundation for better understanding aberrations of reproductive hormone synthesis and action that in turn lead to dysfunctions or diseases of importance to human health with implications for the treatment of infertility or regulation of fertility (see also Project IV).

抑制素和激活素作为垂体FSH合成分泌调节剂和局部作用的研究进展 性腺内的调节因素使它们对维持生殖健康具有关键意义 并表明他们参与了生殖功能障碍(114)。抑制素的中和性增加 动物的卵泡成熟和排卵(115,116)。去除小鼠的α抑制素基因会导致 性腺基质细胞瘤的形成，暗示抑制素是一种肿瘤抑制基因(117)。 相反，抑制素在小鼠体内的过度表达会导致生育力受抑和卵泡发育中断。 (118)。在人类中，抑制素是某些类型卵巢癌的早期标志(6)，这是不适当的 在多囊卵巢综合征中调节(7)，在某些卵巢早熟病例中可能发生突变 失败(8、9)。调节抑制素表达的转录因子也与人类疾病有关(119， 120)，也许最好的例子是性腺和肾上腺功能不全和XY的SF-1突变 性反转(121,122)。 这项建议旨在了解抑制素基因是如何表达和调节的 垂体促性腺激素在卵巢和卵泡颗粒细胞中，侧重于结构特征和 转录因子和共激活因子之间的相互作用对这种调节很重要。图2概述了我们的 目前对抑制素基因在生殖周期中的表达的了解，并指出了关键方面 这一规定，我们计划进一步调查。虽然拟议的实验将集中在 抑制一个亚单位基因，我们希望这些发现能广泛适用于理解促性腺激素和 哺乳动物卵巢中调控基因表达的cAMP依赖的信号通路。这是基本的 这些知识有望为更好地理解生殖异常提供基础。 荷尔蒙的合成和作用，进而导致功能障碍或对人类健康重要的疾病 对不孕不育的治疗或生育调节的影响(另见项目四)。