ROLE OF GLYCOSYLATION IN FSH SIGNALING IN FSH TARGET CELLS

糖基化在 FSH 靶细胞中 FSH 信号传导中的作用

• 批准号: 7651597
• 负责人: JOHN S DAVIS
• 金额: $ 23.09万
• 依托单位: WICHITA 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: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651597
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aging; Aging-Related Process; Aromatase; Binding; Biochemical; Biological; Biological Assay; Biological Models; Cell Line; Cell Proliferation; Cell physiology; Cell secretion; Cells; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Estrogens; Face; Family suidae; Feedback; Female; Fertility; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; G-Protein-Coupled Receptors; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Gonadotropins; Growth; Hormone Responsive; Hormones; Human; Human Follicle Stimulating Hormone; In Vitro; Laboratories; Luteolysis; Maintenance; Mediating; Menopause; Metabolic; Modeling; Oocytes; Osteoclasts; Osteoporosis; Outcome; Ovarian; Ovarian Granulosa Cell; Ovarian hormone; Ovary; Ovulation; Perimenopause; Physiological; Postmenopause; Preparation; Production; Protein Isoforms; Quality of life; Receptor Signaling; Regulation; Reporting; Reproductive Process; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Steroid biosynthesis; Steroids; System; Testing; Time; Tissues; Variant; Woman; Work; age related; base; bone; bone cell; bone loss; bone turnover; corpus luteum; glycosylation; granulosa cell; hypothalamic pituitary axis; improved; indexing; inhibin; innovation; macrophage; monolayer; novel; older women; oocyte maturation; osteoclastogenesis; peptide hormone; pituitary gonadal axis; programs; receptor binding; reproductive; research study; response; steroid hormone

The gonadotropin follicle-stimulating hormone (FSH) is critical for regulating fertility and sex steroid hormone production. Positive and negative feedback systems between gonadotropins and steroid hormones are in place to finely control the reproductive processes of follicle recruitment, ovulation, corpus luteum (CL) development, maintenance, and ultimately CL regression. The aging process results in a decline in fertility and diminished sex steroid hormone levels, the latter of which has considerable metabolic consequences. The glycosylation of FSH is critical for its ability to activate FSH-responsive target cells. Recent evidence indicates that glycoform abundance is under physiological regulation; and importantly new isoforms of FSH have been characterized. Analysis of hFSH preparations revealed that di-glycosylated hFSH is more abundant than tetra-glycosylated hFSH in young women and levels of tetra-glycosylated hFSH are elevated in postmenopausal women. Furthermore, di-glycosylated hFSH appears to have much greater ability to stimulate estrogen secretion than other forms. However, little is known about the cellular signaling mechanisms that occur in granulosa cells that occur as a result of alterations in FSH glycosylation. Our preliminary data indicate that FSH can activate multiple signaling pathways in its target cells. Furthermore, our data suggest that activation of phosphatidylinositol-3-kinase/AKT signaling correlates well with aromatase expression and estrogen secretion, whereas, activation of Erk signaling reduces aromatase and estrogen production. Conversely, the activation of Erk in granulosa cells results in increased proliferative responses at the expense of steroidogenesis. This proposal will test the overall hypothesis that di-glycosylated and tetra-glycosylated hFSH glycoforms provoke qualitative and quantitative differences in cellular signaling pathways, which contribute to altered cellular responses in cells expressing FSH receptors.Aim 1. Determine the efficacy and potency of FSH glycoforms in terms of FSH receptor signaling and steroidogenesis using a homogeneous porcine ovarian granulosa cell monolayer model. Aim 2. Determine how FSH glycoforms control FSH receptor signaling, follicle growth, and steroidogenesis in a well-established whole follicle culture model. Aim 3. Determine FSH glycoform signaling and bone cell function using well-established primary cultures of bone cells and a FSH-responsive bone macrophage-cell line. The ability to employ three relevant but distinct model systems will provide a unique opportunity to discover how FSH glycoform signaling controls the function of FSH-responsive target cells.

促性腺激素卵泡刺激素（FSH）是调节生育和性类固醇的关键 荷尔蒙分泌促性腺激素和类固醇激素之间的正反馈和负反馈系统 激素到位，精细地控制卵泡募集，排卵，体 黄体（CL）的发展，维持，并最终CL消退。衰老过程导致了 在生育和减少性类固醇激素水平，其中后者具有相当大的代谢 后果FSH的糖基化对其激活FSH应答靶细胞的能力至关重要。 最近的证据表明，糖型丰度是在生理调节下;重要的是，新的 FSH的同种型已被表征。对hFSH制剂的分析显示， 在年轻女性中，hFSH比四糖基化hFSH更丰富， 在绝经后妇女中升高。此外，二糖基化hFSH似乎具有更大的 刺激雌激素分泌的能力强于其他形式。然而，人们对细胞信号传导知之甚少， 在颗粒细胞中发生的机制是FSH糖基化改变的结果。我们 初步数据表明FSH可以激活其靶细胞中的多种信号通路。此外，委员会认为， 我们的数据表明，磷脂酰肌醇-3-激酶/AKT信号的激活与 芳香化酶表达和雌激素分泌，而Erk信号传导的激活降低芳香化酶， 雌激素的产生相反，颗粒细胞中Erk的激活导致细胞增殖性增加， 以类固醇合成为代价的反应。这一提议将检验以下总体假设： 双糖基化和四糖基化hFSH糖型引起定性和定量 细胞信号通路的差异，导致细胞反应的改变， FSH受体表达细胞。确定FSH糖型的有效性和效力， 使用同种猪卵巢颗粒细胞的FSH受体信号传导和类固醇生成 单层模型目标2.确定FSH糖型如何控制FSH受体信号传导，卵泡生长， 和类固醇生成的良好建立的全卵泡培养模型。目标3.测定FSH糖型 使用良好建立的骨细胞原代培养物和FSH应答的 骨巨噬细胞系采用三个相关但不同的模型系统的能力将提供一个 发现FSH糖型信号传导如何控制FSH反应靶点功能的独特机会 细胞