Genomic Fingerprint of PGF2alpha and LH actions on the *

描述(申请人提供)：黄体(CL)在其有限的生命周期中经历结构和功能的动态变化。然而，发生在非生育周期末期的自发性黄体溶解的机制(S)，尽管循环中的[黄体生成素]没有明显的下降，仍然没有得到充分的描述。此外，绒毛膜促性腺激素(CG)延长CL寿命的机制仍然是一个谜。CG是一种脑垂体促性腺激素的功能类似物，由胎盘滋养层细胞在生育月经周期中阐述。利用促性腺激素释放激素受体拮抗剂诱导黄体溶解模型，我们发现了几个受黄体生成素调控的新基因，表明黄体生成素应答基因的表达是维持黄体功能的关键。我们最近标准化了一次注射促性腺激素释放激素拮抗剂以诱导黄体溶解，以开展黄体功能动力学研究。积累的实验证据表明，起源于卵巢的前列腺素(PG)F2pha可能在高等灵长类动物中起到黄体素的作用。幸运的是，我们观察到在月经周期的黄体期的某些日子外源性给予PGF2pha后，猴子的黄体功能下降。鉴于这一令人兴奋的发现对阐明自发性黄体溶解的机制具有重要意义，我们假设在非生育周期中，PGF2α细胞内信号干扰了黄体生成素诱导自发性黄体溶解的作用。为了验证这一假说，我们将研究以下目标：(1)阐明与PGF2α作用相关的信号转导机制；(2)研究在非生育周期中，PGF2α激活的信号通路与黄体生成素的细胞内信号串扰以抑制黄体功能的机制。将对猴子CL进行全球基因表达谱分析，以确定在PGF2pha治疗或黄体生成素分泌抑制后的差异表达基因，以确定与黄体溶解相关的信号通路。这两个系统之间的表达模式将通过不同的方法进行研究，以确定与自发黄体溶解相关的生化途径。

DESCRIPTION (provided by applicant): The corpus luteum (CL) undergoes dynamic changes in structure and function during its finite life-span. However, the mechanism(s) responsible for spontaneous luteolysis that occurs at the end of the non-fertile cycle, despite the lack of a discernible decrease in circulating [luteinizing hormone] LH, remains poorly characterized. Also, the mechanism by which the life-span of the CL gets extended by the chorionic gonadotropin (CG), a functional analog of pituitary LH, elaborated by the placental trophoblast in fertile menstrual cycles remains a mystery. Utilizing the GnRH antagonist induced-luteolysis model, we have identified several novel genes whose expressions were regulated by LH in the monkey CL indicating that expressions of genes in response to LH is critical to the maintenance of CL function. We have recently standardized a single injection of GnRH antagonist to induce luteolysis for carrying out studies on the kinetics of luteal function. Accumulated experimental evidence suggests that prostaglandin (PG)F2alpha originating within the ovary might function as luteolysin in higher primates. Fortuitously, we observed a decreased luteal function following exogenous administration of PGF2alpha on certain days of the luteal phase of the menstrual cycle in monkeys. In view of this exciting finding that has implications on elucidating mechanisms of spontaneous luteolysis, we hypothesize that PGF2alpha intracellular signaling interferes with LH action to induce spontaneous luteolysis during non-fertile cycle. To test this hypothesis, the following objectives will be investigated: (1) to elucidate the mechanisms of signal transduction associated with PGF2alpha action; and (2) to investigate the mechanism by which PGF2alpha-activated pathways cross talk with intracellular signaling of LH to curtail luteal function during the non-fertile cycle. Global gene expression profiling analysis on the monkey CL will be performed to identify differentially expressed genes in response to PGF2alpha treatment or after LH secretion inhibition to identify signaling pathways associated with luteolysis. Expression patterns between the two systems will be investigated by various approaches to identify the biochemical pathways associated with spontaneous luteolysis.