Gonadal and extra-gonadal actions of FSH glycoforms in aging

FSH 糖型在衰老过程中的性腺和性腺外作用

基本信息

批准号：
9565031
负责人：
T. RAJENDRA KUMAR
金额：
$ 48.07万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9565031
关键词：
Activins Affect Affinity Age Aging Alleles Asparagine Binding Biochemical Biological Biological Process Bone Density Bone Development Candidate Disease Gene Cells Clinical Development Elderly woman Engineering Estrus Event Female Fertility Follicle Stimulating Hormone Follicle Stimulating Hormone Receptor Gene Expression Profile Genetic Genetic Recombination Genetically Engineered Mouse Genitourinary system Glycoproteins Goals Gonadotropin Hormone Releasing Hormone Half-Life Hormones Human Impairment In Vitro Individual Intervention Knockout Mice Laboratories Lead Ligands Link Mediating Menstrual cycle Morbidity - disease rate Mus Mutation Oocytes Osteoclasts Ovarian Ovarian Follicle Ovarian Granulosa Cell Ovary Peptides Perimenopause Phenotype Physiological Physiology Pituitary Gland Pituitary Gonadotropins Play Postmenopause Production Recombinant Follicle Stimulating Hormone Role Serum Signal Pathway Signal Transduction Specificity Steroids Symptoms Tamoxifen Testing Time Tissues Transgenes Uterine hemorrhage Variant Vasomotor Woman Work age related aged analog base beta Subunit Follicle Stimulating Hormone bone bone aging bone loss bone mass cell type clinically significant folliculogenesis genetic approach glycosylation improved in vivo inhibin molecular size mouse model normal aging novel novel therapeutics poor egg quality prevent psychologic receptor-mediated signaling reproductive senescence sugar translational impact young woman

项目摘要

The long-term goal of this project is to study mechanisms of pituitary control of ovarian and bone function in aging women. Normal ovarian function is dependent on follicle-stimulating hormone (FSH), a pituitary derived heterodimeric glycoprotein consisting of a α-and a β-subunit. Both the subunits are glycosylated with two N- linked sugar chains in each subunit. This fully glycosylated form is designated FSH24. Glycosylation plays a major role in secretion, serum half-life and biological actions of FSH. It is known that glycosylation of pituitary gonadotropins is also estrous/menstrual cycle- and age-specific. Biochemical and physiological studies in several species have identified unique hypo-glycosylated variants consisting of sugar chains only in the α but either one or none on the β subunit. These variants are known as hypo-glycosylated FSH glycoforms and designated as FSH21, FSH18 or FSH15. Most importantly, the ratio of hypo- to fully-glycosylated FSH forms is found age-dependent, with high levels of fully-glycosylated variant predominantly present in peri/post- menopausal women and may contribute to the aging-associated bone loss. However, the distinct in vivo biological functions of these FSH glycoform variants are unknown in normal and aging ovarian and bone physiology. The central hypothesis is that glycosylation on FSH is an age-related switch that changes target tissue specificity from ovary to bone. This hypothesis will be tested using genetically engineered mouse models in two specific Aims. In Aim 1, we will test ovarian development and function progressively with aging using Fshb null mice expressing individual glycosylated forms of FSH. This genetic strategy will allow us to test systematically the in vivo biological actions of each glycosylated FSH variant in ovarian physiology in the absence of endogenous mouse FSH. In Aim 2, first, we will use the FSH glycoform-expressing mice and test bone development as a function of aging. To unequivocally test the direct actions of FSH on bone, in one approach, we will engineer mice in which Fshr will be selectively deleted in osteoclasts by a Cre-lox genetic approach. In a second approach, we will develop a genetically engineered mouse line that permits creating temporal loss of FSH at desired times. Functional analyses with these genetically altered mouse models will identify distinct biological actions of FSH variants in vivo during ovarian aging and by extrapolation, in human ovarian senescence. These novel mouse models will also allow us to directly test whether aging-associated bone loss is dependent on FSH ligand or FSH receptor-mediated signaling in osteoclasts in the bone. Our studies may unravel a novel phenomenon of age-dependent N-glycosylation switch on a pituitary glycoprotein hormone that results in alterations in target tissue specificity (ovary versus bone) and may potentially lead to new therapeutic options for intervention of bone loss in aging women.

该项目的长期目标是研究垂体控制卵巢和骨功能的机制老年女性的正常卵巢功能依赖于促卵泡激素（FSH），一种垂体衍生的激素。由 α- 和 β- 亚基组成的异二聚体糖蛋白，这两个亚基均被两个 N- 糖基化。每个亚基中连接的糖链被称为 FSH24。已知垂体的糖基化在 FSH 的分泌、血清半衰期和生物作用中起主要作用。促性腺激素也是针对发情/月经周期和年龄的生化和生理学研究。一些物种已鉴定出仅在 α 中由糖链组成的独特低糖基化变体，但 β 亚基上有一个或没有，这些变体被称为低糖基化 FSH 糖型。指定为 FSH21、FSH18 或 FSH15 最重要的是，低糖基化 FSH 形式与完全糖基化 FSH 形式的比率为发现年龄依赖性，高水平的完全糖基化变异主要存在于围产期/产后更年期女性可能会导致与衰老相关的骨质流失，但体内情况截然不同。这些 FSH 糖型变体的生物学功能在正常和老化的卵巢和骨骼中尚不清楚生理学的中心假设是 FSH 上的糖基化是一种与年龄相关的开关，可以改变目标。从卵巢到骨骼的组织特异性将使用基因工程小鼠进行测试。在两个具体目标中的模型在目标 1 中，我们将随着衰老逐步测试卵巢发育和功能。使用表达单个 FSH 糖基化形式的 Fshb 缺失小鼠，我们可以测试这种遗传策略。历史上每个糖基化 FSH 变体在卵巢生理学中的体内生物学作用缺乏内源性小鼠 FSH 在目标 2 中，首先，我们将使用表达 FSH 糖型的小鼠进行测试。骨骼发育与衰老的关系明确测试 FSH 对骨骼的直接作用。方法，我们将设计小鼠，其中破骨细胞中的 Fshr 将通过 Cre-lox 基因选择性删除在第二种方法中，我们将开发一种可以创造的基因工程小鼠品系。使用这些基因小鼠模型进行 FSH 在所需时间的暂时损失。确定 FSH 变体在卵巢衰老过程中体内的独特生物学作用，并通过推断在人类中这些新颖的小鼠模型也将使我们能够直接测试是否与衰老相关。骨质流失取决于骨骼中破骨细胞中 FSH 配体或 FSH 受体介导的信号传导。研究可能揭示垂体糖蛋白上年龄依赖性 N-糖基化开关的新现象导致靶组织特异性（卵巢与骨骼）改变的激素，并可能导致干预老年女性骨质流失的新治疗选择。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Illustrating the coupled human-environment system for vulnerability analysis: three case studies.

说明用于脆弱性分析的耦合人类环境系统：三个案例研究。

DOI：
发表时间：
2003-07-08
期刊：
影响因子：
11.1
作者：
Turner 2nd, B L;Matson, Pamela A;McCarthy, James J;Corell, Robert W;Christensen, Lindsey;Eckley, Noelle;Hovelsrud;Kasperson, Jeanne X;Kasperson, Roger E;Luers, Amy;Martello, Marybeth L;Mathiesen, Svein;Naylor, Rosamond;Polsky
通讯作者：
Polsky

The potential connectivity of waterhole networks and the effectiveness of a protected area under various drought scenarios.

水坑网络的潜在连通性和保护区在各种干旱情况下的有效性。

DOI：
发表时间：
2014
期刊：
影响因子：
3.7
作者：
O'Farrill, Georgina;Gauthier Schampaert, Kim;Rayfield, Bronwyn;Bodin, Örjan;Calmé, Sophie;Sengupta, Raja;Gonzalez, Andrew
通讯作者：
Gonzalez, Andrew

Agent-based modeling of deforestation in southern Yucatan, Mexico, and reforestation in the Midwest United States.

基于代理的墨西哥尤卡坦半岛南部森林砍伐和美国中西部重新造林建模。