FSH-Stimulated Signals that Regulate Follicular Maturation

调节卵泡成熟的 FSH 刺激信号

• 批准号: 7936246
• 负责人: Mary E Hunzicker-Dunn
• 金额: $ 30.34万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936246
• 关键词: 1-Phosphatidylinositol 3-Kinase; A kinase anchoring protein; Biological Assay; Boxing; Cell Maturation; Cell Survival; Cell model; Cells; Complex; Contraceptive Agents; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Enzymes; Event; Family; Female; Fertility; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; GAB2 gene; GTP-Binding Proteins; Gene Expression; Gene Family; Gene Targeting; Genetic Transcription; Graafian Follicles; Growth; Individual; Infertility; JUNB gene; LH Receptors; Location; Luteinization; Mediating; Multienzyme Complexes; Ovarian Follicle; Ovulation; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Pituitary Hormones; Pregnancy loss; Process; Protein Kinase; Proteins; Proteomics; Regulation; Signal Transduction; Signaling Protein; Staging; Steroids; Surface; Testing; Time; Transcriptional Activation; Translating; Tyrosine Phosphorylation; Undifferentiated; Western Blotting; base; beta catenin; chromatin immunoprecipitation; effective therapy; genome sequencing; granulosa cell; growth hormone regulating factor; hypothalamic pituitary axis; insight; insulin receptor substrate 1 protein; novel strategies; oocyte maturation; phosphoric diester hydrolase; protein complex; public health relevance; response; steroid hormone; uterine receptivity

DESCRIPTION (provided by applicant): Fertility in females requires controlled maturation of the oocyte, supporting granulosa cells (GCs), and thecal cells that comprise the ovarian follicle. Follicle growth is a dynamic process that demands exquisite regulation. Follicles are restrained at the preantral stage until they are stimulated by the pituitary hormone follicle stimulating hormone (FSH). In response to FSH GCs produce steroid and protein hormones and growth factors that regulate the hypothalamic/pituitary axis and uterine receptivity, and promote oocyte maturation and development of the follicle to a preovulatory phenotype. All of the documented responses to FSH are mediated via cAMP and it's predominate intracellular target, cAMP-dependent protein kinase (PKA). Indeed, GCs offer one of the best examples of a cellular model whose responses are orchestrated by PKA. Signaling by PKA is confined to specific locations in cells by virtue of a family of A-kinase anchoring proteins (AKAPs) that localize pools of PKA, their substrates, and interconnected signaling enzymes. This application focuses on the mechanisms by which PKA integrates transcriptional networks to imitate maturation of GCs. PKA accomplishes this integrating function by phosphorylating substrates that directly regulate transcription or by regulating pathways whose targets regulate transcription. The co-activator beta-catenin is emerging as one potential PKA substrate necessary for activation of a subset of FSH target genes. PKA also phosphorylates an unidentified substrate that directs activation of the phosphatidylinositol-3 kinase (PI-3K) pathway fundamental to GC survival, proliferation, and differentiation. Among the many PI-3K pathway targets, the transcriptional factor FOXO1 (forkhead box O factor 1) requires phosphorylation/inactivation to permit induction of at least a subset of FSH target genes. We postulate that PKA phosphorylates both beta-catenin to activate its co- activator activity and a substrate to direct activation of the PI-3K pathway to activate and inactivate a network of FOXO1-regulated target genes. Aims test the following hypotheses: that a specific AKAP targets a pool of PKA to a multi-enzyme complex that directs activation of PI-3K; that induction of FSH target genes like Lhcgr requires activation of beta-catenin; and that the PI-3K pathway target FOXO1 regulates a network of direct target genes that maintain GCs in an immature stage. Understanding how FSH signals to direct follicular maturation can translate into safer and more effective treatments of infertility and early pregnancy loss as well as new approaches for contraceptive drugs. PUBLIC HEALTH RELEVANCE: FSH signaling to mature follicles to the preovulatory phenotype is required for fertility. Understanding how FSH signals to direct follicular maturation can translate into safer and more effective treatments of infertility and early pregnancy loss as well as new approaches for contraceptive drugs.

描述（由申请人提供）：女性的生育能力需要卵母细胞、支持性颗粒细胞（GC）和构成卵泡的膜细胞的受控成熟。卵泡生长是一个动态过程，需要精细的调节。卵泡在窦前阶段受到抑制，直到受到垂体激素卵泡刺激素（FSH）的刺激。为了响应 FSH，GC 产生类固醇和蛋白质激素以及生长因子，调节下丘脑/垂体轴和子宫容受性，并促进卵母细胞成熟和卵泡发育至排卵前表型。所有记录在案的 FSH 反应都是通过 cAMP 介导的，它是主要的细胞内靶点，即 cAMP 依赖性蛋白激酶 (PKA)。事实上，GC 提供了细胞模型的最佳示例之一，其响应由 PKA 协调。借助 A 激酶锚定蛋白 (AKAP) 家族，PKA 的信号传导被限制在细胞中的特定位置，AKAP 能够定位 PKA、其底物和互连信号酶的池。该应用重点关注 PKA 整合转录网络以模拟 GC 成熟的机制。 PKA 通过磷酸化直接调节转录的底物或通过调节靶标调节转录的途径来实现这种整合功能。共激活剂 β-连环蛋白正在成为激活 FSH 靶基因子集所必需的一种潜在 PKA 底物。 PKA 还可磷酸化一种未识别的底物，该底物可指导磷脂酰肌醇-3 激酶 (PI-3K) 途径的激活，这对 GC 存活、增殖和分化至关重要。在众多 PI-3K 通路靶标中，转录因子 FOXO1（叉头框 O 因子 1）需要磷酸化/失活才能诱导至少一部分 FSH 靶基因。我们假设 PKA 磷酸化 β-连环蛋白以激活其共激活剂活性，并磷酸化底物以指导 PI-3K 途径的激活，从而激活和失活 FOXO1 调节的靶基因网络。目的测试以下假设：特定的 AKAP 将 PKA 库靶向引导 PI-3K 激活的多酶复合物； FSH 靶基因（如 Lhcgr）的诱导需要激活 β-连环蛋白； PI-3K 通路靶标 FOXO1 调节直接靶基因网络，使 GC 维持在未成熟阶段。了解 FSH 信号如何指导卵泡成熟可以转化为更安全、更有效的不孕不育和早期流产治疗方法以及避孕药物的新方法。公共健康相关性：FSH 信号将成熟卵泡转变成排卵前表型是生育能力所必需的。了解 FSH 信号如何指导卵泡成熟可以转化为更安全、更有效的不孕不育和早期流产治疗方法以及避孕药物的新方法。