GnRH Signaling Mechanisms in the Pituitary Gonadotrope

描述（由申请方提供）：促性腺激素释放激素（GnRH）受体的激活启动垂体促性腺激素中的许多复杂信号级联反应。脉冲式GnRH对促性腺激素的节律性刺激是促黄体生成激素和促卵泡激素产生的差异控制的基础，并最终控制生殖。GnRH受体信号级联调节促性腺激素分泌、基因转录和细胞分化。我们已经表明，GnRH调节蛋白质合成和激活未折叠蛋白质反应（UPR），一种保护性反应，以调节蛋白质合成的应激需求。UPR也被炎症和代谢应激信号激活。GnRH受体利用的调节方案对于维持细胞内稳态和对反复出现的GnRH脉冲的敏感性至关重要。为了维持脉冲敏感性和激素合成，促性腺激素必须解决分泌诱导的细胞内变化，增加蛋白质合成以继续满足这些需求，并解决由前一个脉冲激活的信号事件，以允许对下一个脉冲的充分响应。 我们已经确定UPR和翻译的控制作为维持促性腺激素对GnRH的敏感性和生物合成能力的核心要素。我们建议在体外研究这些成分，以确定它们的调节机制，并在实验小鼠模型中确定它们在生殖中的生理作用。普遍定期审议可能提供了生理压力和生殖功能之间的直接联系。具体目标1：促性腺功能中的未折叠蛋白反应。 我们将确定未折叠蛋白反应的三个主要调节因子EIF2AK3和ERN1在正常促性腺细胞功能中的作用。具体目标2：响应GnRH的mRNA再分布机制我们已经证明GnRH引起促性腺细胞中mRNA的再分布。我们将确定再分配的特异性和决定再分配敏感性的因素。具体目标3：小鼠应激反应受损的生理后果我们将通过研究垂体特异性敲除关键UPR调节因子对生殖的影响，来研究未折叠蛋白反应在正常促性腺细胞功能中的作用。

DESCRIPTION (provided by applicant): Activation of the gonadotropin-releasing hormone (GnRH) receptor initiates a number of complex signaling cascades in pituitary gonadotropes. The rhythmic stimulation of gonadotropes by pulsatile GnRH underlies the differential control of luteinizing hormone and follicle-stimulating hormone production, and ultimately the control of reproduction. GnRH receptor signaling cascades regulate gonadotropin secretion, gene transcription and cell differentiation. We have shown that GnRH regulates protein synthesis and activates the unfolded protein response (UPR), a protective response to modulate stressful demands of protein synthesis. The UPR also activated by inflammatory and metabolic stress signals. The regulatory schemes utilized by the GnRH receptor are essential to maintain cell homeostasis and sensitivity to recurring GnRH pulses. To maintain pulse sensitivity and hormone synthesis, gonadotropes must resolve the intracellular alterations induced by secretion, increase protein synthesis to continue to meet these demands, and resolve the signaling events activated by the previous pulse to allow full response to the next. We have identified the UPR and control of translation as central elements maintaining gonadotrope sensitivity to GnRH and biosynthetic capacity. We propose to examine these components in vitro to determine their mechanism of regulation and in experimental mouse models to determine their physiological role in reproduction. The UPR may provide a direct link between physiological stress and reproductive function. Specific Aim 1: The Unfolded Protein Response in gonadotrope function. We will determine the role of the three main regulators of the unfolded protein response, EIF2AK3 and ERN1, in normal gonadotrope cell function Specific Aim 2: Mechanisms of mRNA redistribution in response to GnRH We have demonstrated that GnRH causes a redistribution of mRNA in gonadotropes. We will determine the specificity of redistribution and the factors determining susceptibility to redistribution. Specific Aim 3: Physiological consequences of an impaired stress response in mice We will examine the role of the unfolded protein response in normal gonadotrope cell function by examining the reproductive impact of pituitary-specific knockout of critical UPR regulatory factors.