GnRH Signaling Mechanisms in the Pituitary Gonadotrope

描述(由申请人提供)：促性腺激素释放激素(GnRH)受体的激活在垂体促性腺激素中启动了一些复杂的信号级联反应。搏动性促性腺激素释放激素对促性腺激素的节律性刺激是黄体生成素和卵泡刺激素产生的不同控制，最终控制生殖。GnRH受体信号通路调节促性腺激素的分泌、基因转录和细胞分化。我们已经证明，GnRH调节蛋白质合成并激活未折叠蛋白质反应(UPR)，这是一种调节蛋白质合成应激需求的保护性反应。炎症和代谢应激信号也激活了UPR。GnRH受体所利用的调节机制对于维持细胞内稳态和对反复出现的GnRH脉冲的敏感性是必不可少的。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引起的细胞内变化，增加蛋白质合成以继续满足这些需求，并解决由前一脉冲激活的信号事件以允许对下一脉冲的完全反应。我们已经确定UPR和翻译的控制是维持促性腺激素对GnRH的敏感性和生物合成能力的核心要素。我们建议在体外检测这些成分，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。UPR可能在生理应激和生殖功能之间提供了直接联系。具体目的1：促性腺激素功能中未折叠蛋白的反应。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特定目标2：GnRH反应的mRNA重分布的机制我们已经证明GnRH导致促性腺激素中的mRNA重分布。我们将确定再分配的特异性和决定再分配易感性的因素。具体目标3：小鼠应激反应受损的生理后果我们将通过检测脑垂体特异性敲除关键的UPR调节因子对生殖的影响，来检验未折叠蛋白反应在正常促性腺细胞功能中的作用。 与公共健康相关：为了保持正常的生殖激素分泌，并对环境提示做出正确反应，脑下垂体细胞必须将细胞压力降至最低，并适应持续分泌激素的需求。我们正在研究细胞用来适应压力和保持正常细胞功能的机制。这些调节途径对于确保适当的生殖激素合成和生殖成功是必不可少的。

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. PUBLIC HEALTH RELEVANCE: To preserve normal reproductive hormone production and to respond correctly to environmental cues, pituitary cells must minimize cellular stress and adapt to the demand of continued hormone production. We are investigating the mechanisms cells use to adapt to stress and preserve normal cell function. These regulatory pathways are essential to assure proper reproductive hormone synthesis and reproductive success.