ROLE OF GLYCOSYLATION IN FSH SIGNALING IN FSH TARGET CELLS

促性腺激素卵泡刺激素(FSH)是调节生育和性激素的关键。 荷尔蒙的产生。促性腺激素与类固醇之间的正、负反馈系统 荷尔蒙被用来精细地控制卵泡招募、排卵、体的生殖过程。 黄体(CL)的发育、维持和最终的CL回归。老化的过程导致下降 生育力和性激素水平下降，后者有相当大的新陈代谢 后果。FSH的糖基化对其激活FSH反应的靶细胞的能力至关重要。 最近的证据表明，糖类丰度受到生理调节；重要的是，新的 卵泡刺激素的亚型已被鉴定。对hFSH制剂的分析表明，二糖基化 在年轻女性中，hFSH比四糖基化的hFSH更丰富，并且四糖基化的hFSH水平 在绝经后妇女中升高。此外，二糖基化的hFSH似乎有更多的 刺激雌激素分泌的能力强于其他形式。然而，对细胞信号转导知之甚少。 由于卵泡刺激素糖基化改变而发生在颗粒细胞中的机制。我们的 初步数据表明，FSH可以激活其靶细胞中的多条信号通路。此外， 我们的数据表明，磷脂酰肌醇-3-激酶/AKT信号的激活与 芳香酶的表达和雌激素的分泌，而ERK信号的激活则减少了芳香酶和雌激素的分泌。 雌激素的产生。相反，颗粒细胞中erk的激活导致增殖性增加。 以类固醇生成为代价的反应。这一提议将检验总体假设，即 二糖基化和四糖基化hFSH糖型引起定性和定量 细胞信号通路的差异，这有助于改变细胞的反应 表达FSH受体的细胞。目的1.测定FSH糖体的有效性和效力 同种猪卵巢颗粒细胞FSH受体信号转导和类固醇合成的研究 单层模型。目的2.确定FSH糖形式如何控制FSH受体信号、卵泡生长、 以及成熟的完整卵泡培养模型中的类固醇生成。目的3.测定卵泡刺激素糖体 利用成熟的骨细胞原代培养和FSH反应的信号和骨细胞功能 骨巨噬细胞系。使用三个相关但不同的模型系统的能力将提供 发现FSH糖型信号如何控制FSH反应靶点功能的难得机会 细胞。

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.