Activin and Inhibin Signaling and Reproduction

激活素和抑制素信号传导和复制

• 批准号: 7416768
• 负责人: WYLIE W. VALE
• 金额: $ 145.3万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7416768
• 关键词: Activin; Inhibin; Signaling; Reproduction

This Program Project, comprised of 3 Projects and 2 Cores, explores the signaling mechanisms of activins, BMPs, inhibins and their receptors and binding proteins as they modulate the reproductive and other systems. Project I (Vale) recently identified the proteoglycan, betaglycan, as a putative inhibin co-receptor. This project will investigate the mechanisms by which inhibin interacts with betaglycan and activin receptors to antagonize activin and selected BMPs. Furthermore, the physiologic importance of betaglycan will be tested by immunoneutralization or disruption of its expression in vitro and in vivo. Project I will characterize betaglycan variants and seek additional inhibin co-receptors. Project II (Choe) has solved the X-ray crystallographic structure of the type II receptor extracellular ligand-binding domain (ActRII- ECD) both alone and in a complex with the activin paralog, BMP-7. The structure of BMP-7 with its inhibitory binding protein, noggin, has also been solved. Project II proposes to elucidate additional structures, including triple complexes, comprising activins or BMPs bound to their type II and/or type I ECDs as well as inhibin bound to ActRII and/or betaglycan ECDs. As additional structural information is provided by Project II it will be used by Projects I and Ill to further characterize the structure/function relationships between inhibins, activins, BMPs and their receptors. Project III (Fischer) uses computer modeling and X-ray structure data, obtained in close collaboration with Project II, to design mutant ligands and receptors to be tested for their effects on ligand:receptor binding interactions. Activin mutants will be used to test hypotheses regarding interactions with type II and type I activin receptors and follistatin. Core A (Vale) provides administrative and computer support, evaluation of progress and coordinates interactions with the Advisory Panel and NICHD staff. Core B (Fischer, Rivier, Choe & Vale) provides technical support and reagents, including antisera towards activin/inhibin signaling molecules, and conducts RIAs for pituitary and gonadal hormones. This Core provides synthetic peptides and expresses and purifies recombinant activin and inhibin and various other proteins including receptor components. The Core characterizes native and recombinant proteins by automated sequencing and mass spectrometry. This Program brings together a diversity of approaches to address fundamental issues surrounding activin and BMP signaling and their counter-regulation by inhibin and binding proteins. Because of the physiologic and pathophysiologic significance of activins, BMPs, and inhibins, these studies should serve to illuminate potential means for the control of human fertility and management of medical disorders.

该项目由3个项目和2个核心组成，探索激活素，BMP，BMPs及其受体和结合蛋白的信号传导机制，因为它们调节生殖和其他系统。 项目I（Vale）最近鉴定了蛋白聚糖β聚糖作为推定的甜菜碱共受体。本项目将研究BMPs与β聚糖和激活素受体相互作用以拮抗激活素和选定BMP的机制。此外，β聚糖的生理重要性将通过免疫中和或其体外和体内表达的破坏来测试。项目I将表征β聚糖变体并寻找额外的β-受体。项目II（Choe）已经解决了单独的II型受体胞外配体结合结构域（ActRII-ECD）和与激活素paraminase（BMP-7）的复合物的X射线晶体学结构。BMP-7及其抑制性结合蛋白头蛋白的结构也已得到解决。项目II提出阐明另外的结构，包括三重复合物，其包含与其II型和/或I型ECD结合的激活素或BMP以及与ActRII和/或β聚糖ECD结合的BMPs。由于项目II提供了额外的结构信息，因此项目I和III将使用这些信息进一步表征骨形成素、激活素、BMP及其受体之间的结构/功能关系。 项目III（Fischer）使用与项目II密切合作获得的计算机建模和X射线结构数据，设计突变配体和受体，以测试其对配体：受体结合相互作用的影响。激活素突变体将用于检验关于与II型和I型激活素受体和卵泡抑素相互作用的假设。核心A（淡水河谷）提供行政和计算机支持，评估进展情况，并协调与咨询小组和NICHD工作人员的互动。Core B（Fischer，Rivier，Choe & Vale）提供技术支持和试剂，包括针对激活素/腺苷二酸信号分子的抗血清，并进行垂体和性腺激素的RIA。该核心提供合成肽，并表达和纯化重组激活素和腺苷酸以及包括受体组分在内的各种其他蛋白质。Core通过自动测序和质谱法表征天然和重组蛋白质。该计划汇集了多种方法，以解决围绕激活素和BMP信号传导及其由BMPin和结合蛋白的反调节的基本问题。由于激活素、骨形成蛋白和骨形成蛋白的生理和病理生理意义，这些研究应有助于阐明控制人类生育和管理医学疾病的潜在手段。

项目成果

Three forms of gonadotropin-releasing hormone characterized from brains of one species.

• DOI: 10.1073/pnas.91.25.12081
• 发表时间: 1994-12
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: J. Powell;Yonathan Zohar;A. Elizur;Minkyu Park;Wolfgang H. Fischer;A. Craig;J. Rivier;David A. Lovejoy;N. Sherwood

Inhibin-mediated feedback control of follicle-stimulating hormone secretion in the female rat.

• DOI: 10.1126/science.3092356
• 发表时间: 1986-10
• 期刊: Science
• 影响因子: 56.9
• 作者: C. Rivier;J. Rivier;W. Vale

Molecular and functional characterization of GnRH receptors cloned from rat pituitary and a mouse pituitary tumor cell line.

• DOI: 10.1006/bbrc.1993.1335
• 发表时间: 1993-03
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: M. Perrin;L. Bilezikjian;C. Hoeger;Cynthia J. Donaldson;J. Rivier;Yaira Haas;W. Vale

Gonadal tumorigenesis in transgenic mice bearing the mouse inhibin alpha-subunit promoter/simian virus T-antigen fusion gene: characterization of ovarian tumors and establishment of gonadotropin-responsive granulosa cell lines.

• DOI: 10.1210/mend.9.5.7565808
• 发表时间: 1995-05
• 期刊: Molecular endocrinology
• 作者: K. Kananen;M. Markkula;E. Rainio;J. Su;A. Hsueh;I. Huhtaniemi

Effect of the serotonin reuptake inhibitor fluoxetine on corticotropin-releasing factor and vasopressin secretion into hypophysial portal blood.

血清素再摄取抑制剂氟西汀对促肾上腺皮质激素释放因子和垂体门静脉血中加压素分泌的影响。

• DOI: 10.1016/0006-8993(83)91189-7
• 发表时间: 1983
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Gibbs,DM;Vale,W
• 通讯作者: Vale,W