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

• 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
• 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

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.

本项目的长期目标是研究垂体控制卵巢和骨功能的机制， 老年妇女正常的卵巢功能依赖于卵泡刺激素（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。两个亚基都被两个N-糖基化， 每个亚基中的糖链相连。这种完全糖基化的形式被命名为FSH 24。糖基化作用 在FSH的分泌、血清半衰期和生物学作用中起主要作用。已知垂体糖基化 促性腺激素也具有发情/月经周期特异性和年龄特异性。生物化学和生理学研究 几个物种已经鉴定出独特的低糖基化变体，其糖链仅在α中， β亚基上有一个或没有。这些变体被称为低糖基化FSH糖型， 命名为FSH 21、FSH 18或FSH 15。最重要的是，低糖基化FSH与完全糖基化FSH的比例是 发现具有年龄依赖性，高水平的完全糖基化变体主要存在于糖尿病/糖尿病后 绝经期妇女，并可能导致与年龄相关的骨质流失。然而，不同的体内 这些FSH糖型变体在正常和老化卵巢和骨中的生物学功能尚不清楚 physiology.中心假设是FSH上的糖基化是一个与年龄相关的开关， 从卵巢到骨骼的组织特异性。这一假设将用基因工程小鼠进行测试。 有两个具体目标。在目标1中，我们将随着年龄的增长逐步检测卵巢的发育和功能 使用表达单个糖基化形式FSH的Fshb缺失小鼠。这种遗传策略将使我们能够测试 系统地研究了每种糖基化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FSH糖型表达小鼠并测试 骨骼发育是随着年龄增长而变化的。为了明确测试FSH对骨骼的直接作用，在一个 方法，我们将通过Cre-lox基因工程改造小鼠，其中Fshr将在破骨细胞中选择性缺失。 approach.在第二种方法中，我们将开发一种基因工程小鼠品系， FSH在所需时间暂时丧失。对这些基因改变的小鼠模型进行功能分析， 在人类卵巢老化过程中，通过外推法鉴定FSH变体在体内的不同生物学作用 卵巢衰老这些新的小鼠模型也将使我们能够直接测试是否与衰老有关。 骨丢失依赖于骨中破骨细胞中FSH配体或FSH受体介导的信号传导。我们 研究可能揭示一种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）改变并可能导致 干预老年妇女骨丢失的新治疗选择。

项目成果

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。

• DOI: 10.1073/pnas.0705802104
• 发表时间: 2007
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Manson,StevenM;Evans,Tom
• 通讯作者: Evans,Tom

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: 10.1371/journal.pone.0095049
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: O'Farrill,Georgina;GauthierSchampaert,Kim;Rayfield,Bronwyn;Bodin,Örjan;Calmé,Sophie;Sengupta,Raja;Gonzalez,Andrew
• 通讯作者: Gonzalez,Andrew