FSH-Stimulated Signals that Regulate Follicular Maturation

描述（由申请人提供）：女性生育力需要卵母细胞、支持颗粒细胞（GC）和卵泡膜细胞（包括卵泡）的受控成熟。卵泡生长是一个动态的过程，需要精细的调控。卵泡在窦前阶段被抑制，直到它们被垂体激素卵泡刺激素（FSH）刺激。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为排卵前表型。所有记录的对FSH的反应都是通过cAMP介导的，cAMP是主要的细胞内靶点，cAMP依赖性蛋白激酶（PKA）。事实上，GC提供了一个最好的例子，细胞模型的反应是由PKA编排。PKA的信号传导被限制在细胞中的特定位置，这是由于A-激酶锚定蛋白（AKAP）家族将PKA、其底物和相互连接的信号传导酶的库定位。该应用程序的重点是PKA整合转录网络模仿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点调节转录的途径来实现这种整合功能。辅激活因子β-连环蛋白是一种潜在的PKA底物，是激活FSH靶基因亚群所必需的。PKA还磷酸化一种未鉴定的底物，其指导对GC存活、增殖和分化至关重要的磷脂酰肌醇-3激酶（PI-3K）途径的活化。在许多PI-3K途径靶点中，转录因子FOXO1（叉头盒O因子1）需要磷酸化/失活以诱导至少一个FSH靶基因亚组。我们假设PKA磷酸化β-连环蛋白以激活其共激活因子活性，并磷酸化底物以直接激活PI-3K途径，从而激活和阻断FOXO 1调节的靶基因网络。目的测试以下假设：特定AKAP将PKA库靶向多酶复合物，指导PI-3K的激活; FSH靶基因（如Lhcgr）的诱导需要β-连环蛋白的激活; PI-3K途径靶点FOXO 1调节直接靶基因网络，将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，更有效的治疗不孕症和早期妊娠丢失以及避孕药物的新方法。公共卫生相关性：卵泡成熟为排卵前表型的FSH信号是生育所必需的。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期妊娠丢失以及避孕药物的新方法。

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.