Genomic Fingerprint of PGF2alpha/LH actions on luteal

PGF2α/LH 对黄体作用的基因组指纹

• 批准号: 7046342
• 负责人: Rajagopala Sridaran
• 金额: $ 7.1万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-26 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046342
• 关键词: Macaca; apoptosis; bioinformatics; biological signal transduction; blood tests; chorionic gonadotropin; corpus luteum; estradiol; gene expression; gene expression profiling; gonadotropin releasing factor; hormone inhibitor; hormone regulation /control mechanism; luteinizing hormone; menstrual cycle; microarray technology; northern blottings; polymerase chain reaction; progesterone; prostaglandin F; steroid biosynthesis

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.

描述（由申请人提供）：黄体（CL）在其有限的生命周期内经历了结构和功能的动态变化。然而，尽管循环[黄体生成素]LH缺乏明显的减少，但在非生育周期结束时发生的自发黄体溶解的机制仍然不清楚。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是垂体LH的功能类似物，在月经周期中由胎盘滋养细胞详细阐述。利用GnRH拮抗剂诱导的黄体溶解模型，我们在猴子CL中发现了几个受LH调控的新基因，这表明响应LH的基因表达对CL功能的维持至关重要。我们最近标准化了单次注射GnRH拮抗剂来诱导黄体溶解，以进行黄体功能动力学研究。积累的实验证据表明，在高等灵长类动物中，起源于卵巢的前列腺素（PG）F2alpha可能具有叶黄素的功能。幸运的是，我们观察到在月经周期的黄体期的某些天外源性给药PGF2alpha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黄体溶解机制具有重要意义，我们假设PGF2alpha细胞内信号干扰黄体生成素的作用，从而在非生育周期诱导自发黄体溶解。为了验证这一假设，将研究以下目标：(1)阐明与PGF2alpha作用相关的信号转导机制；(2)研究pgf2α激活的途径与细胞内LH信号相互作用，从而抑制非生育周期黄体功能的机制。将对猴子CL进行全局基因表达谱分析，以鉴定PGF2alpha治疗或LH分泌抑制后的差异表达基因，以鉴定与黄体溶解相关的信号通路。两个系统之间的表达模式将通过各种方法进行研究，以确定与自发黄体溶解相关的生化途径。