GNRH SIGNALING MECHANISMS IN THE PITUITARY GONADOTROPE

垂体前叶的多种内分泌细胞群是调节内分泌功能的关键因素。明确垂体前叶的内分泌细胞与调节垂体功能的下丘脑的神经分泌细胞的关系和功能整合，对于理解内分泌效应器调控的不同组织和器官系统之间的复杂相互作用是至关重要的。本研究的目的是探讨促性腺激素细胞--垂体前叶在神经肽激素促性腺激素释放激素(GnRH)刺激下改变蛋白质合成和细胞增殖的机制。最近在培养的垂体促性腺激素细胞模型αT3细胞中的实验确定了GnRH受体(一种G蛋白偶联受体)激活通常由受体酪氨酸激酶(如胰岛素和其他生长因子受体)使用的信号转导级联的机制。我们已经扩展了这些研究，以证明GnRH通过另一种途径影响细胞生理学，该途径直接调节mRNA，并通过激活新的DNA合成来启动增殖。在第一个目标中，我们将定义翻译信号通路的细胞成分，并研究GnRH刺激对该通路的调节。在第三个目标中，我们将建立一个独特的转基因小鼠模型系统，用于详细分析垂体中的GnRH信号。GnRH对翻译和细胞增殖的调节对该激素在垂体前叶促性腺细胞发育中的作用具有重要意义。这些研究将明确GnRH在正常功能的垂体促性腺激素中可能具有的直接和重要的作用，并为激素对靶受体承载组织的作用机制提供重要的见解。

The multiple endocrine cell populations of the anterior pituitary are key participants in the coordination of endocrine function. Defining the relationships and functional integration of the endocrine cells of the anterior pituitary with the neurosecretory cells of the hypothalamus that regulate pituitary function is essential for understanding the complex interplay of widely differing tissues and organ systems regulated by endocrine effectors. The aims of this proposal investigate the mechanism of a novel regulatory pathway utilized by the gonadotrope cells the anterior pituitary that alters both protein synthesis and cellular proliferation in response to stimulation by the neuronal peptide hormone gonadotropin-releasing hormone (GnRH). Recent experiments in a cultured cell model of pituitary gonadotropes, alphaT3 cells, have defined the mechanism by which the GnRH receptor, a G-protein coupled receptor, activates a signal transduction cascade normally utilized by receptor tyrosine kinases such as the receptors for insulin and other growth factors. We have extended these studies to demonstrate that GnRH influences cellular physiology by an additional pathway that directly regulates of mRNA and initiates proliferation by activation of new DNA synthesis. In the first aim we will define the cellular components of the translation signaling pathway and investigate the regulation of this pathway by GnRH stimulation. In the third aim we will develop a unique transgenic mouse model system for detailed analysis of GnRH signaling in the pituitary. The regulation of translation and cell proliferation by GnRH has important implications for the role of this hormone in the development of the gonadotrope cells of the anterior pituitary. These studies will define the direct and significant role that GnRH may have in the normal function pituitary gonadotropes, and provide important insight into the mechanism of hormone action on target receptor-bearing tissues.