The Aging Pituitary/Gonadal Axis

衰老的垂体/性腺轴

• 批准号: 9755286
• 负责人: GEORGE R BOUSFIELD
• 金额: $ 170.92万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755286
• 关键词: Address; Affect; Age; Age-Related Bone Loss; Aging; Binding; Binding Sites; Biological; Biological Assay; Blood Circulation; Cell Line; Cell model; Cells; Chinese Hamster Ovary Cell; Data; Diagnosis; Elements; Estradiol; Estrogens; Family suidae; Female; Fertility; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Funding; Gene Expression; Genes; Genetic Models; Genitourinary system; Gonadotropins; Human; Human Follicle Stimulating Hormone; Impairment; In Vitro; Individual; Infertility; Knowledge; Mass Spectrum Analysis; Menopause; Menstrual cycle; Menstruation; Microscopy; Molecular Conformation; Molecular Weight; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Osteoclasts; Ovarian; Ovary; Pattern; Physiological; Pituitary Gland; Postmenopause; Preparation; Procedures; Progress Reports; Reporting; Resolution; Role; Sampling; Signal Pathway; Signal Transduction; Steroid biosynthesis; Symptoms; Testing; Tissues; Transgenic Mice; Urine; Uterine hemorrhage; Variant; Vasomotor; Woman; age related; assisted reproduction; base; bone; bone loss; bone mass; bone metabolism; diagnostic biomarker; glycosylation; granulosa cell; in vivo; in vivo Bioassay; next generation sequencing; older women; pituitary gonadal axis; programs; psychologic; receptor; receptor binding; reproductive; reproductive function; reproductive senescence; response; small molecule; young woman

Abstract The beginning of the menopausal transition lacks suitable diagnostic markers. The transition is attended by significant morbidity including irregular reproductive cycles, dysfunctional uterine bleeding, urogenital changes, impaired fertility, declining bone mass, vasomotor symptoms, and psychological impairment. The long-term objective of this project is to understand the role of follicle-stimulating hormone (FSH) glycosylation variants hFSH21 and hFSH24 in aging. Young women possess more hypo-glycosylated hFSH21 than fully-glycosylated hFSH24, while older women possess less hFSH21. As both glycoforms are found in urine, both enter the circulation where they affect gonadal and non-gonadal targets. In the previous funding period we determined that hFSH21 is much more active than hFSH24 in binding FSHR, activating gonadal target cells in vitro, and stimulating the ovary in vivo. In contrast, hFSH24 is much more active than hFSH21 in activating osteoclast differentiation. Thus, our overall hypothesis is, in the face of a senescing ovary, the additional switch from hFSH21 to hFSH24 further compromises fertility and may contribute to bone loss. Each project will test various aspects of this hypothesis via the following specific aims: 1. Determine the mechanism(s) by which partial glycosylation of hFSH leads to significantly increased FSHR binding. Our working hypothesis is that hFSH21 and small molecule binding alter FSHR conformation, making more FSH binding sites available to both glycoforms, thus increasing bioactivity. An exciting element is collaborative super resolution microscopy studies that will monitor FSHR oligomerization directly. 2. Define the different signaling pathways activated by FSH glycoforms in traditional gonadal targets as well as in bone, a nontraditional target cell. Under this aim, Project 2 will compare FSH glycoform activation of murine or human granulosa cells or cell lines, and osteoclast precursors. Our working hypothesis is that hFSH21 is more active than hFSH24 in gonadal target cells, while the reverse is true for non-gonadal target cells. The age-related shift in glycoform ratio thus has important physiological consequences. 3. Use genetic models to study the role of FSH glycoforms in the aging ovary and age-related bone loss. Under this aim, FSH hypo-glycosylated glycoforms will be evaluated by Project 3 for their ability to rescue Fshb null female mice from infertility and their effects on bone loss. Our working hypothesis is the age-related shift from FSH21 to FSH24 has deleterious effects on ovarian function, yet promotes osteoclast activation. These projects will be supported by two scientific cores. Core B will provide critical FSH glycoform preparations to all projects. Core C will assist in analyzing mass spectrometry data, provide next generation sequencing (NGS) and analyze NGS data. Together, the projects will provide new knowledge about the role of FSH glycoforms in reproductive aging that can be used to diagnose the onset of the menopausal transition, and evidence to support or refute the controversial role of FSH in bone loss in aging women.

抽象的 更年期过渡的开始缺乏合适的诊断标记。过渡是 出席了明显的发病率，包括不规则的生殖周期，功能失调的子宫出血， 泌尿生殖器的变化，生育能力受损，骨骼质量下降，血管舒缩症状和心理 损害。该项目的长期目标是了解刺激激素的作用 （FSH）衰老中的糖基化变体HFSH21和HFSH24。年轻女性具有更多的低糖基化 HFSH21比完全糖基化的HFSH24，而老年女性的HFSH21较少。由于发现了两个糖型 在尿液中，两者都进入影响性腺和非基达靶标的循环。在以前的资金中 时期我们确定HFSH21在结合FSHR中比HFSH24更活跃，激活性腺靶 体外细胞在体内刺激卵巢。相反，HFSH24比HFSH21在 激活破骨细胞分化。因此，我们的总体假设是面对卵巢的卵巢 从HFSH21到HFSH24的额外切换进一步损害了生育能力，并可能导致骨质流失。每个 项目将通过以下特定目的检验该假设的各个方面：1。确定 HFSH的部分糖基化导致FSHR结合显着增加的机制。我们的 工作假设是HFSH21和小分子结合改变了FSHR构象，使得更多的FSH 可用于两种糖型的结合位点，从而提高生物活性。令人兴奋的元素是协作 超级分辨率显微镜研究将直接监测FSHR低聚。 2。定义不同的 传统性腺靶标和骨骼中FSH糖型激活的信号通路 非传统目标细胞。在此目标下，项目2将比较鼠或人类的FSH糖型激活 颗粒细胞或细胞系以及破骨细胞前体。我们的工作假设是HFSH21更活跃 在性腺靶细胞中，HFSH24比HFSH24，而反向对于非贡达靶细胞是正确的。与年龄有关的转变 因此，在糖型比中具有重要的生理后果。 3。使用遗传模型研究 卵巢老龄化和与年龄相关的骨质流失中的FSH糖型。在此目的下，FSH低糖基化 糖型将通过项目3评估，以使其从不育和 它们对骨质流失的影响。我们的工作假设是从FSH21到FSH24的年龄相关的转变有害 对卵巢功能的影响，但促进破骨细胞激活。这些项目将得到两个 科学核心。核心B将为所有项目提供关键的FSH糖型制剂。核心将有助于 分析质谱数据，提供下一代测序（NGS）并分析NGS数据。 这些项目将共同提供有关FSH糖型在生殖衰老中的作用的新知识 可用于诊断更年期过渡的开始，并证明支持或反驳 FSH在衰老女性中的骨质流失中有争议的作用。