Endocrine and Growth Factor Regulation in the Pituitary

描述（由申请方提供）：控制垂体促性腺激素细胞促性腺激素产生的激素影响的微妙平衡包括激活素和卵泡抑素（来自性腺和促性腺激素本身）、下丘脑释放激素GnRH的脉动模式和类固醇激素反馈。在这个修订后的申请中，我们的重点将是激活素，GnRH和类固醇激素调节促性腺细胞中FSH β亚基基因表达的分子机制。我们的总体假设是激活素对FSH β亚基基因的适当调节至关重要，包括GnRH和类固醇激素的完全调节。我们的模型系统是小鼠，这是由于使用遗传技术可以容易地操纵基因组，并且能够利用表达FSH、LH、激活素、卵泡抑素和GnRH、激活素、雄激素、孕激素和糖皮质激素受体的永生化小鼠促性腺激素细胞系。在具体目标1中，我们将重点关注激活素诱导FSH β亚基基因的分子机制，以及激活素信号在Smad缺陷小鼠体内促性腺细胞中的生理作用。在具体目标2中，我们将研究FSH β亚基基因的紧张性和脉动性调节的分子机制，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，我们将讨论类固醇激素信号在FSH β亚基基因调节中的作用，重点是雄激素，孕激素和糖皮质激素。与GnRH的情况一样，FSH β亚基基因的完全类固醇激素诱导依赖于促性腺细胞中的激活素自分泌张力，并与激活素的诱导协同。我们将在分子水平上研究这种相互作用的基础。最后，我们将利用靶向破坏小鼠促性腺激素细胞中的类固醇受体基因来评估这些受体在体内垂体中的作用。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调节中的整合。因此，肽类激素，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的相互作用将使用的分子，细胞，遗传和小鼠技术的医疗设备进行调查，其目标是发展一个详细的了解介导生殖功能的分子机制在垂体的水平。

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.