FSH-Stimulated Signals that Regulate Follicular Maturation

调节卵泡成熟的 FSH 刺激信号

基本信息

批准号：
8321001
负责人：
Mary E Hunzicker-Dunn
金额：
$ 29.07万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8321001
关键词：
1-Phosphatidylinositol 3-Kinase A kinase anchoring protein Biological Assay Boxing Cell Maturation Cell Survival Cell model Cells Complex Contraceptive Agents Coupled 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

1-Phosphatidylinositol 3-Kinase A kinase anchoring protein Biological Assay Boxing Cell Maturation Cell Survival Cell model Cells Complex Contraceptive Agents Coupled 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

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项目摘要

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控制卵母细胞的成熟，支撑颗粒细胞（GCS）和构成卵巢卵泡的胸腔细胞。卵泡生长是一个动态过程，需要精致的调节。卵泡在尿下阶段受到约束，直到被垂体激素卵泡刺激激素（FSH）刺激。响应FSH GC会产生类固醇和蛋白质激素以及调节下丘脑/垂体轴和子宫接受度的生长因子，并促进卵母细胞成熟和卵泡发展为卵巢型表型。所有对FSH的记录反应都是通过cAMP介导的，它是细胞内靶标，cAMP依赖性蛋白激酶（PKA）。确实，GC提供了细胞模型的最佳例子之一，该模型由PKA精心策划。 PKA的信号通过A-激酶锚定蛋白（AKAP）的家族限制在细胞中的特定位置，该蛋白（AKAP）定位PKA的池，其底物和相互连接的信号传导酶。该应用程序着重于PKA整合转录网络以模仿GC的成熟的机制。 PKA通过磷酸化的底物来实现这种整合功能，该底物直接调节转录或调节靶标调节转录的途径。共激活β-catenin成为激活FSH靶基因子集所需的一种潜在的PKA底物。 PKA还磷酸化了一个未鉴定的底物，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，增殖和分化基本的基础。在许多PI-3K途径目标中，转录因子FOXO1（叉子盒O因子1）需要磷酸化/灭活，以允许至少诱导FSH靶基因的至少子集。我们假设PKA磷酸化两种β-catenin以激活其共激活剂活性和底物，以直接激活PI-3K途径，以激活和灭活FOXO1调节的靶基因网络。目的测试以下假设：特定的AKAP靶向PKA池源于指导PI-3K激活的多酶复合物； FSH靶基因（如LHCGR）的诱导需要激活β-catenin。 PI-3K途径靶标FOXO1调节直接靶基因的网络，该靶基因将GC保持在不成熟阶段。了解指导卵泡成熟的信号如何转化为不育和早期妊娠丧失的更安全，更有效的治疗方法，以及避孕药的新方法。公共卫生相关性：对成熟卵泡的FSH信号传导至排卵前表型才能生育。了解指导卵泡成熟的信号如何转化为不育和早期妊娠丧失的更安全，更有效的治疗方法，以及避孕药的新方法。