Inhibin Actions on Reproductive Target Tissues

抑制素对生殖目标组织的作用

• 批准号: 7462400
• 负责人: Teresa K Woodruff
• 金额: $ 27.73万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462400
• 关键词: Address; Anabolism; Antral; Biochemical; Biological; Biological Assay; Biological Models; Blood Vessels; Cell Line; Cells; Chimera organism; Chinese Hamster Ovary Cell; Disease; Endocrine; Ensure; Enzymes; Feedback; Fertility; Follicle Stimulating Hormone; Glycoproteins; Grant; Hormones; In Vitro; Inhibin A; Intervention; Isomerism; Ligands; Link; Liquid substance; MDCK cell; Menopause; Methods; Molecular Weight; Ovarian; Ovarian Follicle; Ovarian Granulosa Cell; Ovary; Pathway interactions; Pattern; Pituitary Gland; Post-Translational Protein Processing; Process; Production; Protein Glycosylation; Protein Isoforms; Protein Subunits; Proteolytic Processing; Rattus; Recombinant Inhibin A; Regulation; Research; Research Proposals; Role; Route; Secretory Vesicles; Signal Transduction; Time; Tissues; Woman; Work; bioprocess; chemotherapy; glycosylation; granulosa cell; in vivo; in vivo Model; inhibin; inhibin B; insight; men; mouse Numb protein; receptor binding; reproductive; reproductive function; research study; restraint; sertoli cell; theca cell

DESCRIPTION (provided by applicant): The objective of this research proposal is to understand the biosynthetic pathways leading to inhibin secretion from ovarian granulosa cells. The most recognized action of inhibin is to suppress FSH production and secretion by the pituitary gonadotrope in vitro and in vivo. Inhibin levels are regulated during the reproductive cycle to ensure normal FSH-dependent follicle recruitment. Little is known regarding the cellular pathways leading to inhibin biosynthesis, yet, it is the thesis of this grant renewal that these pathways are responsible for the accurate production of this key ovarian feedback hormone and are vital to normal reproductive function. Inhibin A and inhibin B are produced by the granulosa cell of the ovary, however, the secretion patterns for these ligands are distinct, suggesting an underlying control over biosynthesis and release that has not been previously investigated. In addition, the precise mechanism by which many granulosa cell products are targeted toward the antral fluid or the vascular theca cell compartment is not well understood. Our preliminary studies have identified differential secretion patterns of inhibin A and inhibin B during the rat reproductive cycle, described differential compartmentalization of inhibin subunit protein in granulosa cells of developing follicles, and revealed that the biosynthetic processing of inhibin isoforms is regulated. These preliminary studies and the results of the past five years of work suggest that the cellular machinery that regulates inhibin biosynthesis and processing is important to inhibin action and must be investigated in order to more completely understand the function of this ligand in women and men. We hypothesize that inhibin bioactivity relies on post-translational modification including N-linked glycosylation, protein specific routing signals contained in pro-hormone domains, and bioprocessing enzymes that convert bioinactive pro-ligand into mature, bioactive inhibin. There are three interrelated experimental aims in this proposal that will address the central hypothesis and its tenets. These studies are expected to provide insight into the control of inhibin synthesis and release and contribute to a more complete understanding of normal fertility and the mechanisms that underlie fertilityrelated diseases in women resulting from inappropriate hormone action.

描述（由申请人提供）：本研究计划的目的是了解导致卵巢颗粒细胞分泌白蛋白的生物合成途径。最公认的作用是在体外和体内抑制垂体促性腺激素FSH的产生和分泌。抑制素水平在生殖周期中受到调节，以确保正常的FSH依赖性卵泡募集。人们对导致抑制素生物合成的细胞途径知之甚少，然而，本次资助更新的论点是，这些途径负责这种关键卵巢反馈激素的准确产生，并且对正常生殖功能至关重要。 抑制素A和抑制素B是由卵巢颗粒细胞产生的，然而，这些配体的分泌模式是不同的，这表明对生物合成和释放的潜在控制以前没有研究过。此外，许多颗粒细胞产物靶向窦液或血管膜细胞室的确切机制还不清楚。我们的初步研究已经确定了在大鼠生殖周期中，Escherichin A和Escherichin B的不同分泌模式，描述了Escherichin亚基蛋白在发育卵泡的颗粒细胞中的差异区室化，并揭示了Escherichin异构体的生物合成过程受到调节。这些初步的研究和过去五年的工作结果表明，细胞的机制，调节bisobin的生物合成和加工是重要的bisobin行动，必须进行调查，以更全面地了解这种配体在女性和男性的功能。我们假设，tubin生物活性依赖于翻译后修饰，包括N-连接的糖基化，蛋白质特异性路由信号中包含的激素原结构域，和生物加工酶转化成成熟的，生物活性的tubin的生物活性的前配体。在这个提议中有三个相互关联的实验目标，将解决中心假设及其原则。这些研究有望深入了解对甜菜碱合成和释放的控制，并有助于更全面地了解正常生育能力以及因激素作用不当而导致妇女生育相关疾病的机制。

项目成果

Ovarian follicle development requires Smad3.

• DOI: 10.1210/me.2003-0414
• 发表时间: 2004-09
• 期刊: Molecular endocrinology
• 作者: D. Tomić;K. Miller;H. Kenny;T. Woodruff;P. Hoyer;J. Flaws

Phylogenomic analyses reveal the evolutionary origin of the inhibin alpha-subunit, a unique TGFbeta superfamily antagonist.

• DOI: 10.1371/journal.pone.0009457
• 发表时间: 2010-03-04
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhu J;Braun EL;Kohno S;Antenos M;Xu EY;Cook RW;Lin SJ;Moore BC;Guillette LJ Jr;Jardetzky TS;Woodruff TK
• 通讯作者: Woodruff TK

Inhibin α-subunit N terminus interacts with activin type IB receptor to disrupt activin signaling.

抑制素α-亚基N 末端与激活素IB 型受体相互作用，破坏激活素信号传导。

• DOI: 10.1074/jbc.m111.293381
• 发表时间: 2012
• 期刊: The Journal of biological chemistry
• 作者: Zhu,Jie;Lin,SJack;Zou,Chao;Makanji,Yogeshwar;Jardetzky,TheodoreS;Woodruff,TeresaK
• 通讯作者: Woodruff,TeresaK

Maintaining fertility in young women with breast cancer.

• DOI: 10.1007/s11864-010-0116-2
• 发表时间: 2009-12
• 期刊: CURRENT TREATMENT OPTIONS IN ONCOLOGY
• 影响因子: 4.3
• 作者: Hulvat, Melissa C.;Jeruss, Jacqueline S.
• 通讯作者: Jeruss, Jacqueline S.

Role of PCSK5 expression in mouse ovarian follicle development: identification of the inhibin α- and β-subunits as candidate substrates.

• DOI: 10.1371/journal.pone.0017348
• 发表时间: 2011-03-08
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Antenos M;Lei L;Xu M;Malipatil A;Kiesewetter S;Woodruff TK
• 通讯作者: Woodruff TK