Horomone Control of Gene Expression in the Gonadotrope

激素对促性腺激素基因表达的控制

• 批准号: 7052247
• 负责人: PAMELA L MELLON
• 金额: $ 33.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052247
• 关键词: activins; cell line; gene expression; genetic transcription; genetically modified animals; gonadotropin releasing factor; gonadotropins; hormone regulation /control mechanism; intermolecular interaction; laboratory mouse; pituitary gland; steroid hormone

The delicate balance of hormonal influences that governs gonadotropin production by the pituitary gonadotrope cell includes activin and follistatin (derived from the gonad and from the gonadotrope itself), the pulsatile pattern of the hypothalamic releasing hormone, GnRH, and gonadal steroid hormone feedback. In Research Project I, our focus will be the cellular and molecular mechanisms of activin, GnRH, and steroid hormone regulation of LH and FSH beta-subunit gene expression in the gonadotrope. Our model system is the mouse, due to the facile manipulations of the genome attainable by genetic technology and the ability to exploit our immortal mouse gonadotrope cell lines that express FSH, LH, activin, follistatin, and the receptors for GnRH, activin, androgens, glucocorticoids, and progestins. In Specific Aim 1, we will focus on the induction of the FSH and LH beta-subunit genes by activin and the physiological role of activin signaling in the gonadotrope in vivo in Smad deficient mice. In Specific Aim 2, we will investigate the molecular mechanism for tonic and pulsatile regulation of the LH and FSH beta-subunit genes and study the dependence of GnRH action on the activin autocrine loop in culture. In Specific Aim 3, we will address the roles of steroid hormone signaling in regulation of the FSH beta-subunit gene in culture focusing on androgens, glucocorticoids, and progestins. As is the case for GnRH, steroid hormone induction of the FSH beta-subunit gene is dependent upon activin autocrine tone in the gonadotrope and synergistic with induction by activin. We will investigate the basis of this interaction at the molecular level. Finally, we will utilize targeted disruption of the steroid receptor genes in the gonadotrope in mice to assess the role of these receptors in the pituitary in vivo. Our overall goal is to address the integration of activin, GnRH, and steroid hormone signaling in the regulation of LH and FSH in the gonadotrope. Thus, the interplay of peptide hormones, growth factors, steroids, receptors, and hypothalamic releasing factors in controlling gonadotropin gene expression will be investigated using the armamentarium of molecular, cellular, genetic, and mouse technologies with the goal of developing a detailed understanding of the molecular mechanisms mediating reproductive function at the level of the pituitary.

控制垂体促性腺细胞产生促性腺激素的激素影响的微妙平衡包括激活素和卵泡抑素（源自性腺和促性腺激素本身）、下丘脑释放激素 GnRH 的脉动模式和性腺类固醇激素反馈。在研究项目 I 中，我们的重点是激活素、GnRH 和类固醇激素调节促性腺激素中 LH 和 FSH β 亚基基因表达的细胞和分子机制。我们的模型系统是小鼠，因为可以通过遗传技术轻松操作基因组，并且能够利用表达 FSH、LH、激活素、卵泡抑素和受体的永生小鼠促性腺激素细胞系 用于 GnRH、激活素、雄激素、糖皮质激素和孕激素。在具体目标 1 中，我们将重点关注激活素对 FSH 和 LH β 亚基基因的诱导，以及激活素信号在 Smad 缺陷小鼠体内促性腺激素中的生理作用。在具体目标 2 中，我们将研究 LH 和 FSH β 亚基基因的强直和脉动调节的分子机制，并研究 GnRH 作用对培养物中激活素自分泌环的依赖性。在具体目标 3 中，我们将探讨类固醇激素信号传导在培养物中 FSH β 亚基基因调节中的作用，重点关注雄激素、糖皮质激素和孕激素。与 GnRH 的情况一样，FSH β 亚基基因的类固醇激素诱导依赖于促性腺激素中激活素的自分泌张力，并与激活素的诱导具有协同作用。我们将在分子水平上研究这种相互作用的基础。最后，我们将利用小鼠促性腺激素中类固醇受体基因的靶向破坏来评估这些作用 体内垂体的受体。我们的总体目标是解决激活素、GnRH 和类固醇激素信号在促性腺激素中 LH 和 FSH 调节中的整合问题。因此，将使用分子、细胞、遗传和小鼠技术的设备来研究肽激素、生长因子、类固醇、受体和下丘脑释放因子在控制促性腺激素基因表达中的相互作用，目的是详细了解促性腺激素基因表达的机制。介导垂体水平生殖功能的分子机制。