FSH-Stimulated Signals that Regulate Follicular Maturation

描述（由申请人提供）：女性的生育能力需要控制卵母细胞、支持颗粒细胞（GCs）和构成卵泡的鞘细胞的成熟。卵泡生长是一个动态的过程，需要精细的调节。卵泡在胃窦前阶段受到抑制，直到它们受到垂体激素促卵泡激素（FSH）的刺激。在FSH的作用下，GCs产生类固醇和蛋白激素以及调节下丘脑/垂体轴和子宫容受性的生长因子，促进卵母细胞成熟和卵泡发育到排卵前表型。所有记录的FSH应答都是通过cAMP及其主要的细胞内靶点cAMP依赖性蛋白激酶（PKA）介导的。事实上，GCs提供了一个细胞模型的最佳例子，其反应是由PKA精心策划的。通过a激酶锚定蛋白（AKAPs）家族，PKA信号被限制在细胞中的特定位置，该家族定位PKA池、它们的底物和相互连接的信号酶。本应用着重于PKA整合转录网络以模仿GCs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其靶标调节转录的途径来实现这种整合功能。协同激活剂β -连环蛋白正在成为激活FSH靶基因子集所必需的潜在PKA底物。PKA还磷酸化一种未知的底物，该底物指导磷脂酰肌醇-3激酶（PI-3K）途径的激活，这是GC存活、增殖和分化的基础。在许多PI-3K通路靶点中，转录因子FOXO1（叉头盒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 -连环蛋白以激活其辅激活因子活性，并磷酸化一个底物以直接激活PI-3K通路，从而激活和灭活fox01调节的靶基因网络。目的验证以下假设：特定的AKAP将PKA池靶向到指导PI-3K激活的多酶复合物上；诱导FSH靶基因如Lhcgr需要激活-连环蛋白；PI-3K通路的靶点FOXO1调节了一个直接靶基因网络，该网络维持了未成熟阶段的GCs。了解FSH信号如何指导卵泡成熟，可以转化为更安全、更有效的治疗不孕症和早孕流产，以及避孕药的新方法。公共卫生相关性：卵泡刺激素信号传递到成熟卵泡到排卵前表型是生育所必需的。了解FSH信号如何指导卵泡成熟，可以转化为更安全、更有效的治疗不孕症和早孕流产，以及避孕药的新方法。

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.