Endocrine and Growth Factor Regulation in the Pituitary

描述(申请人提供)：调节垂体促性腺激素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素(来自性腺和促性腺激素本身)、下丘脑释放激素、促性腺激素释放激素和类固醇激素反馈的脉动模式。在这个修订的应用中，我们的重点将放在激活素、促性腺激素释放激素和类固醇激素调节促性腺激素中FSHβ亚单位基因表达的分子机制上。我们的总体假设是，激活素对FSHβ亚基基因的适当调控至关重要，包括GnRH和类固醇激素的全面调控。我们的模型系统是小鼠，这是因为使用基因技术可以轻松地操纵基因组，并能够利用我们永生化的小鼠促性腺激素细胞系，这些细胞系表达FSH、LH、激活素、卵泡素以及GnRH、激活素、雄激素、孕激素和糖皮质激素的受体。在特定的目标1中，我们将重点研究激活素诱导FSHβ亚基基因的分子机制，以及激活素信号在体内Smad缺陷小鼠促性腺激素中的生理作用。在特定的目标2中，我们将研究FSHβ亚基基因紧张性和脉动性调节的分子机制，并研究GnRH的作用依赖于培养中的激活素自分泌环。在特定的目标3中，我们将讨论类固醇激素信号在FSHβ亚单位基因调控中的作用，重点是雄激素、孕激素和糖皮质激素。与GnRH的情况一样，类固醇激素对FSHβ亚基基因的完全诱导依赖于促性腺激素中的激活素自分泌，并与激活素的诱导协同作用。我们将在分子水平上研究这种相互作用的基础。最后，我们将利用靶向干扰小鼠促性腺激素中的类固醇受体基因来评估这些受体在体内脑垂体中的作用。我们的总体目标是解决激活素、促性腺激素释放激素和类固醇激素信号在促性腺激素中FSH调节中的整合。因此，将利用分子、细胞、遗传和小鼠技术来研究多肽激素、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方面的相互作用，目的是在脑垂体水平上详细了解调节生殖功能的分子机制。

DESCRIPTION (provided by applicant): 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 steroid hormone feedback. In this revised application, our focus will be on the molecular mechanisms of activin, GnRH, and steroid hormone regulation of FSH beta-subunit gene expression in the gonadotrope. Our overall hypothesis is that activin is critical for appropriate regulation of the FSH beta-subunit gene including full regulation by GnRH and steroid hormones. Our model system is the mouse, due to the facile manipulations of the genome attainable using genetic technology and the ability to exploit our immortalized mouse gonadotrope cell lines that express FSH, LH, activin, follistatin, and the receptors for GnRH, activin, androgens, progestins, and glucocorticoids. In Specific Aim 1, we will focus on the molecular mechanisms of induction of the FSH beta-subunit gene 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 mechanisms for tonic and pulsatile regulation of the FSH beta-subunit gene 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 focusing on androgens, progestins, and glucocorticoids. As is the case for GnRH, full 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 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.