Role of Egr-1 in Corpus Luteum Function

描述（由申请方提供）：黄体（CL）功能过早中断导致妊娠受阻、周期不规则和生殖效率总体下降。在哺乳动物中，包括灵长类动物和人类，PGF/2 α被认为是诱导CL消退（黄体溶解）的触发因素，由此孕酮合成受到抑制，黄体结构退化，月经或发情周期恢复。然而，尽管广泛的研究表明其生理作用，PGF/2 α诱导CL消退的细胞和分子机制仍然知之甚少。我们的初步数据表明，Egr-1 mRNA和蛋白的表达上调CL在PGF/2 α诱导的黄体溶解在体内和在PGF/2 α处理的黄体细胞在体外。Egr-1基因属于一组立即早期反应基因，编码含锌指的DNA结合转录因子。最近的研究表明，Egr-1可能介导卵泡生长，排卵和黄体化过程中的增殖和/或分化的分子程序。然而，在各种细胞系中的研究也表明，Egr-1蛋白可以诱导各种促凋亡蛋白的上调和激活，表明Egr-1是促凋亡信号级联的活性部分。然而，控制Egr-1表达的机制和Egr-1在CL中的作用尚不清楚。我们推测Egr-1通过诱导关键的促凋亡蛋白的表达和减少孕酮分泌在PGF/2 α的作用中起重要作用。提出了两个具体目标：具体目标1：确定对照和PGF/2 α处理的牛黄体细胞中Egr-1的细胞定位和活性。具体目标二：确定Egr-1蛋白在调节促凋亡蛋白（如PTEN和TGF β 1）和牛黄体细胞孕酮分泌中的作用。通过确定Egr-1对PGF/2 α治疗的调节和功能，拟议的研究将有助于我们理解CL消退的生物生理学和黄体功能障碍的病理生理学。这项研究的完成将为开发新的治疗策略提供有价值的信息，用于调节生育能力和管理由黄体功能不足和/或卵巢疾病引起的不孕症。

DESCRIPTION (provided by applicant): Premature disruption of corpus luteum (CL) function results in the prevention of pregnancy, irregular cyclicity, and an overall decrease in reproductive efficiency. In mammals, including primates and human, PGF/2alpha is believed to be the trigger that induces the regression (luteolysis) of the CL, whereby progesterone synthesis is inhibited, the luteal structure involutes, and the menstrual or estrus cycle resumes. However, despite extensive studies demonstrating its physiological role, the cellular and molecular mechanisms of PGF/2alpha-induced CL regression remain poorly understood. Our preliminary data demonstrate that the expression of Egr-1 mRNA and protein is up regulated in the CL during PGF/2alpha-induced luteolysis in vivo and in PGF/2alpha-treated luteal cells in vitro. The Egr-1 gene belongs to a group of immediate early response genes, which encode zinc finger-containing DNA-binding transcription factors. Recent studies suggest that Egr-1 may mediate molecular programs of proliferation and/or differentiation during follicle growth, ovulation, and lutenization. However, studies in various cell lines have also shown that Egr-1 protein can induce the up-regulation and activation of various pro-apoptotic proteins, suggesting that Egr-1 is an active part of the apoptotic-signaling cascade. Nevertheless, the mechanisms controlling Egr-1 expression and the role of Egr-1 in the CL are not known. We hypothesize that Egr-1 plays an important role in the action of PGF/2alpha by inducing the expression of key proapoptotic proteins and reducing progesterone secretion. Two specific aims are proposed: Specific Aim 1: To determine the cellular location and activity of Egr-1 in control and PGF/2alpha-treated bovine luteal cells. Specific Aim 2: To determine the role of Egr-1 protein in the regulation of pro-apoptotic proteins, such as PTEN, and TGFbeta1, and progesterone secretion in bovine luteal cells. By determining the regulation and function of Egr-1 in response to PGF/2alpha treatment, the proposed study will facilitate our understanding of the bio-physiology of CL regression and pathophysiology of luteal dysfunction. The completion of this study will provide valuable information in developing new therapeutic strategies for the regulation of fertility and the management of infertility caused by inadequate luteal function and/or ovarian disorders.