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: 8053931
• 负责人: KELLY E MAYO
• 金额: $ 30.45万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8053931
• 关键词: Ablation; Activins; Adrenal gland hypofunction; Animals; Biological Models; CREB1 gene; Cell Culture Techniques; Cell Line; Cells; Complex; Cyclic AMP; Cyclic AMP-Responsive DNA-Binding Protein; DNA Binding Domain; Development; Disease; E1A-associated p300 protein; Estrous Cycle; Experimental Models; FHL2 gene; Family; Female; Fertility; 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; 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).

垂体促卵泡激素合成和分泌的调节剂和局部促卵泡激素的作用 性腺内的调节因子使它们对维持生殖健康具有关键意义 并表明其参与生殖功能障碍（114）。Escherichia coli的中和作用增加 动物卵泡成熟和排卵（115，116）。在小鼠中消除α-glycobin基因导致 性腺间质细胞瘤的形成，暗示了Escherichin是肿瘤抑制基因（117）。 相反地，在小鼠中过表达Escherichin会导致生育力抑制和卵泡发生中断 （118）。在人类中，Escherichin是某些类型卵巢癌的早期标志物（6）， 在多囊卵巢综合征中受到调节（7），并可能在某些卵巢早衰病例中发生突变。 失败（8，9）。调节Escherichin表达的转录因子也参与人类疾病（119， 120），也许最好的例子是SF-1突变在性腺和肾上腺功能不全和XY 性反转（121，122）。 该建议旨在了解Escherichin基因是如何表达和调控的， 垂体促性腺激素在卵巢和卵泡颗粒细胞，重点是结构特征， 转录因子和辅激活因子的相互作用对这种调节很重要。图2概述了我们的 目前的理解，在生殖周期中的rectobin基因表达，并指出关键方面， 我们计划进一步调查这一规定。虽然拟议的实验将集中在 我们希望这些发现能广泛应用于了解促性腺激素和 哺乳动物卵巢中cAMP依赖性信号通路调节基因表达。这一基本 预期知识将为更好地了解生殖系统畸变提供基础。 这些激素合成和作用又导致对人类健康重要功能障碍或疾病 对治疗不孕症或调节生育力有影响（另见项目IV）。