GnRH Signaling Mechanisms in the Pituitary Gonadotrope

描述（由申请人提供）：了解构成生殖内分泌轴的组织的发育和调节对了解生殖功能至关重要。控制生殖功能的中枢调节激素是神经肽促性腺激素释放激素I （GnRH）。GnRH I的主要靶点是垂体前叶的促性腺激素。促性腺激素的搏动性GnRH刺激导致异二聚体促性腺激素的合成和释放增加，促黄体生成素和促卵泡激素进入全身循环。在之前的资助期间，我们描述了GnRH受体翻译控制的新特性。翻译控制是一种直接调节基因表达的手段，特别适合于体内GnRH脉冲幅度和频率的快速变化。在这个更新申请中，我们的目标是全面了解GnRH的作用，通过改变促性腺激素蛋白合成来解释促性腺激素基因表达的短期变化。我们的目标是对促性腺激素中介导翻译控制的GnRH信号传导机制的基本理解。然后，我们将定义翻译控制特异性的结构基础，并扩展我们的研究，以调查脉动性在基因调控中的作用。

DESCRIPTION (provided by applicant): Understanding the development and regulation of the tissues that comprise the reproductive endocrine axis is essential to understanding reproductive function. The central regulatory hormone controlling reproductive function is the neuropeptide gonadotropin-releasing hormone I (GnRH). The principal target of GnRH I is the population of gonadotropes in the anterior pituitary. Pulsatile GnRH stimulation of gonadotropes results in increased synthesis and release of the heterodimeric gonadotropin hormones Luteinizing Hormone and Follicle-Stimulating Hormone into the general circulation. During the previous funding period we described the novel property of translational control by the GnRH receptor. Translational control is a means of direct regulation of gene expression that is uniquely suited to the rapid in vivo changes in GnRH pulse amplitude and frequency. In this renewal application, it is our goal to develop a thorough understanding of GnRH action that accounts for short-term changes in gonadotropin gene expression through alterations in gonadotropin protein synthesis. Our aims are directed toward a basic understanding of the mechanisms of GnRH signaling that mediate translational control in gonadotropes. We will then define the structural basis for the specificity of translation control, and extend our studies to investigate the role of pulsatility in gene regulation. Aim 1: Regulation of translation by GnRH. We will define the targets of GnRH action that mediate translational control in a gonadotrope cell line. We will confirm our findings in primary pituitary culture and in a novel transgenic mouse model. Aim 2: Specificity of mRNA utilization by GnRH. We will determine the sensitivity of gonadotropespecific genes to translational control to establish the specificity of regulation through this mechanism. We will determine the molecular basis for this specificity. Aim 3: Regulation of gonadotropin synthesis by pulsatile GnRH. We hypothesize that translation and transcription are differentially regulated by differing GnRH pulse regimes. We will test this and alternate models of regulation by determination of the degree of regulatory component activation and determination of the role of negative feedback signaling in modulating the response to GnRH stimulation.