The Aging Pituitary-Gonadal Axis

衰老的垂体-性腺轴

• 批准号: 8245738
• 负责人: GEORGE R BOUSFIELD
• 金额: $ 123.36万
• 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/8245738
• 关键词: 21 year old; Age; Aging; Bioinformatics; Biological; Biological Assay; Bone Resorption; Cell Culture Techniques; Clinic; Communication; Development; Dose; Female infertility; Fertility; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Genes; Human; Human Follicle Stimulating Hormone; Infertility; Internet; Knockout Mice; Laboratories; Lead; Menstrual cycle; N-Glycosylation Site; Oligosaccharides; Oocytes; Outcomes Research; Ovarian; Ovary; Perimenopause; Pituitary Gland; Polysaccharides; Postmenopause; Preparation; Process; Receptor Activation; Recombinants; Relative (related person); Reporting; Research Personnel; Services; Signal Transduction; Source; Testing; Woman; Work; data sharing; glycosylation; in vivo; interest; mouse model; mutant; novel; older women; pituitary gonadal axis; receptor binding; reproductive function; response

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（由应用程序提供）：要求提供五年的支持以研究老化的垂体 - 卵巢轴。我们试图通过刺激叶片的骑马（FSH）来了解垂体 - 诺伊属的交流。众所周知，与年轻女性相比，在35岁以上的女性中，生育率下降。不育诊所报告说，老年妇女对外源FSH制剂的反应性降低。该项目将集中于卵巢衰老对两个主要人（H）FSH糖型相对丰度变化的反应。具有α亚基和β亚基寡糖的经典HFSH被指定为四糖基化的HFSH，而只有α亚基寡糖的新型HFSH糖型被指定为DI-Glycosylated HFSH。与四糖基化的HFSH相比，21-24岁的妇女表达更多的二糖基化HFSH，围绝经内妇女表达的二糖基化HFSH略微少一些，而绝经后女性表达原发性四甲状腺糖基化的HFSH。项目1将研究月经周期中HFSH糖基型相对抽象的变化，这些变化与FSH受体结合和激活的聚糖调节的年龄和研究机制的增加有关。项目2将比较卵巢中各种信号转导测定中HFSH糖型的活性，以确定可能增强DI-糖基化HFSH生物学活性的可能机制。两种糖型对骨骼分辨率的差异作用也将研究。项目3将创建鼠标模型，以测试两个HFSH糖型对于生殖功能所必需的假设。双HFSH糖基化突变体将取代正常的MFSH基因。这条线将与FSH null小鼠交叉，以查看是否可以挽救女性不育症。纯化的HFSH糖型也将在体内使用FSH NULL小鼠在体内进行测试。 WSU FSH流程核心实验室（Core B）将为所有项目提供纯净的纯化HFSH糖型。最初的产品将是Di-糖基化的HFSH和四糖基化的HFSH，所有科学项目都很感兴趣，但其他来源无法获得。重组双糖基化的HFSH将首先表达，这是由于自然来源的抽象较低。 Core B将在每个占有的N-糖基化位点表征聚糖群，从而提供具有已知的糖基化糖基型，而不是假定的糖基化差异。核心B还将为项目调查人员提供细胞培养和测定服务。 WSU生物信息学核心（Core C）将通过Internet为所有研究人员易于访问数据共享平台。这项研究的结果将更好地理解降低卵巢反应的机制，而衰老可能会导致更有效的FSH制剂来治疗不孕症。尽管目前可用的准备工作在年轻女性中效果很好，但她们在老年妇女中越来越无效，需要更高剂量并长时间给药但产生较少的卵母细胞。