The Aging Pituitary-Gonadal Axis

衰老的垂体-性腺轴

• 批准号: 8056584
• 负责人: GEORGE R BOUSFIELD
• 金额: $ 123.28万
• 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/8056584
• 关键词: Aging; Pituitary; Gonadal; Axis

DESCRIPTION (provided by applicant): Five years of support are requested to study the aging pituitary ovarian axis. We seek to understand pituitary-ovarian communication via follicle-stimulating hormone (FSH). It is well known that in women over the age of 35 fertility declines compared with younger women. Infertility clinics report decreased responsiveness of older women to exogenous FSH preparations. This project will focus on the response of the aging ovary to a change in relative abundance of two major human (h) FSH glycoforms. The classic hFSH possessing both alpha subunit and beta subunit oligosaccharides is designated tetra-glycosylated hFSH and a novel hFSH glycoform possessing only alpha subunit oligosaccharides is designated di-glycosylated hFSH. Women aged 21-24 express more di-glycosylated hFSH than tetra-glycosylated hFSH, perimenopausal women express slightly less di-glycosylated hFSH, while post-menopausal women express primarily tetra-glycosylated hFSH. Project 1 will investigate the changes in relative abundance of hFSH glycoforms during the menstrual cycle that are associated with increasing age and study mechanisms for glycan modulation of FSH receptor binding and activation. Project 2 will compare the activities of hFSH glycoforms in a variety of signal transduction assays in the ovary in order to identify possible mechanisms that enhance the biological activity of di-glycosylated hFSH. The differential effects of both glycoforms on bone resorption will also be studied. Project 3 will create mouse models to test the hypothesis that both hFSH glycoforms are necessary for reproductive function. A double hFSH¿ glycosylation mutant will replace the normal mFSH¿ gene. This line will be crossed with FSH¿ null mice to see if it can rescue female infertility. Purified hFSH glycoforms will also be tested in vivo using FSH null mice. The WSU FSH process core laboratory (Core B) will provide well characterized purified hFSH glycoforms, to all projects. The initial products will be di-glycosylated hFSH and tetra-glycosylated hFSH, which are of interest to all the scientific projects, but are not available from other sources. Recombinant di-glycosylated hFSH will be expressed first, due to low abundance in natural sources. Core B will characterize glycan populatlons at each occupied N-glycosylation site, thereby providing fully characterized glycoforms with known, rather than assumed glycosylation differences. Core B will also provide cell culture and assay services to project investigators. The WSU bioinformatics core (Core C) will provide a data-sharing platform readily accessible to all investigators via the internet. The outcome of this research will be a better understanding of the mechanisms for reduced ovarian responsiveness with aging that may lead to the development of more effective FSH preparations for treating infertility. While currently available preparations work well in young women, they become increasingly ineffective in older women, requiring higher doses and prolonged administration yet producing fewer oocytes.

描述（由申请人提供）：需要五年的支持来研究老化的垂体卵巢轴。我们试图了解垂体-卵巢通过卵泡刺激素（FSH）的沟通。众所周知，35岁以上妇女的生育率与年轻妇女相比有所下降。不孕症诊所报告老年妇女对外源性FSH制剂的反应性降低。该项目将重点关注衰老卵巢对两种主要人类（h）FSH糖型相对丰度变化的反应。具有α亚基和β亚基寡糖两者的经典hFSH被指定为四糖基化hFSH，并且仅具有α亚基寡糖的新型hFSH糖型被指定为二糖基化hFSH。21-24岁的女性表达更多的双糖基化hFSH比四糖基化hFSH，围绝经期女性表达略少的双糖基化hFSH，而绝经后女性主要表达四糖基化hFSH。项目1将研究月经周期中与年龄增长相关的hFSH糖型相对丰度的变化，并研究FSH受体结合和激活的聚糖调节机制。项目2将比较hFSH糖型在卵巢中各种信号转导试验中的活性，以确定增强二糖基化hFSH生物活性的可能机制。还将研究两种糖型对骨吸收的不同影响。项目3将建立小鼠模型，以检验两种hFSH糖型对生殖功能都是必需的这一假设。双hFSH <$糖基化突变体将取代正常的mFSH <$基因。这一品系将与FSH基因敲除小鼠杂交，看看它是否能挽救女性不育症。纯化的hFSH糖型也将使用FSH缺失小鼠进行体内检测。WSU FSH工艺核心实验室（核心B）将为所有项目提供充分表征的纯化hFSH糖型。最初的产品将是二糖基化hFSH和四糖基化hFSH，这是所有科学项目的兴趣，但不能从其他来源获得。由于天然来源的丰度较低，重组二糖基化hFSH将首先表达。核心B将表征每个被占据的N-糖基化位点处的聚糖群体，从而提供具有已知而非假定的糖基化差异的完全表征的糖型。核心B还将为项目研究者提供细胞培养和分析服务。WSU生物信息学核心（Core C）将提供一个数据共享平台，所有研究人员均可通过互联网访问。这项研究的结果将更好地了解卵巢反应性随年龄增长而降低的机制，这可能导致开发更有效的FSH制剂来治疗不孕症。虽然目前可用的制剂在年轻女性中效果良好，但它们在老年女性中变得越来越无效，需要更高的剂量和长期给药，但产生的卵母细胞较少。