Prostaglandin Synthesis and Action in the Primate Corpus Luteum

灵长类黄体中前列腺素的合成和作用

• 批准号: 7900867
• 负责人: Jon D Hennebold
• 金额: $ 38.29万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-27 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900867
• 关键词: Ablation; Address; Adult; Agonist; Angiogenic Factor; Apoptotic; Arachidonic Acids; Biochemical; Cell physiology; Cells; Characteristics; Chorionic Gonadotropin; Complex; Contraceptive methods; Corpus Luteum Maintenance; Coupled; DNA Microarray Chip; Data; Defect; Development; Dinoprost; Dinoprostone; Disease; Domestic Animals; Endocrine Glands; Enzymes; Etiology; Event; Female; Functional disorder; Gene Expression; Generations; Genes; Genome; Gonadotropins; Hormones; Human; Infertility; Infusion procedures; Knowledge; Lead; Length; Lipids; Longevity; Luteal Cells; Luteal Phase; Luteinizing Hormone; Luteolysis; Macaca; Macaca mulatta; Maintenance; Mediating; Menstrual cycle; Menstruation; Metabolism; Molecular; Monkeys; Oocytes; Ovarian; PTGS2 gene; Physiological; Physiology; Pituitary Gland; Play; Pregnancy; Pregnancy Maintenance; Primates; Principal Investigator; Production; Progesterone; Prostaglandin E Receptor; Prostaglandin Receptor; Prostaglandins; Proteins; Protocols documentation; Publishing; Regulation; Research; Rodent; Role; Rupture; Serum; Signal Transduction; Structure; Testing; Time; Tissues; Uterus; Weight; Woman; abstracting; cell growth regulation; corpus luteum; cyclooxygenase 2; granulosa cell; in vivo; inhibitor/antagonist; insight; mammalian genome; novel; novel strategies; premature; primate development; programs; receptor; research study; restoration; steroid hormone

Program Director/Principal Investigator (Last, First, Middle): Hennebold, Jon PHS 398/2590 (Rev. 11/07) Page Continuation Format Page ABSTRACT The long-term objective of this research is to define the mechanisms occurring within the primate corpus luteum (CL) that are critical for its development and regression. Evidence obtained from nonprimate species indicates that prostaglandins (PGs) regulate luteal structure-function, but their role in primate luteal physiology have not been defined. Recent preliminary data have demonstrated that the expression of PGE2 synthesis (prostaglandin-endoperoxide synthase 2 or PTGS2; microsomal PGE2 synthase-1 or PTGES) and signaling (PGE2 receptor 3 or PTGER3) components peak in the rhesus macaque CL through the period of its development. Moreover, expression of the PGE2 synthesizing and signaling components significantly decreased preceding the period of functional regression of the CL, which also coincided with increasing levels of PGF2_ receptor (PTGFR) expression. Thus, experiments will be performed to test the hypothesis that PGE2 actions are critical for primate luteal development, while PGF2_ serves as a critical intraluteal initiator and/or effector of luteolysis. Studies using rhesus macaques are proposed that will assess the role PGE2 signaling plays in the development of the primate CL (Aim 1) and evaluate whether PGF2_ signaling is required for the demise of the CL at the end of the luteal phase (Aim 2). Protocols blocking intraluteal PG synthesis via a PTGS2 selective inhibitor will determine their role in CL development. The ablation of PG synthesis in the developing CL will be combined with the restoration of PTGER3 signaling through the use of a selective PTGER3 agonist. The intraluteal delivery of a PTGFR antagonist prior to the onset of luteal regression will establish the role of PGF2_ in luteolysis. Daily concentrations of serum progesterone, first day of menses, and CL weight will be used to evaluate luteal function and lifespan. Histochemical markers of apoptotic, endothelial, and steroidogenic cells will be used for morphologic analysis of CL structure, while the expression of LH-regulated steroidogenic and angiogenic factors will be quantified to evaluate the relationship between PG signaling and luteal function. These studies will provide novel insight into the role of PG actions in luteal development and regression in primates. Such an understanding of PG involvement in the regulation of luteal structure-function may aid in our undestanding of infertility or other disorders associated with luteal dysfunction.

项目总监/首席研究员（最后，第一，中间）：Hennebold，Jon PHS 398/2590（修订版 11/07） 页面延续 格式页面 抽象的 这项研究的长期目标是确定灵长类动物体内发生的机制 黄体（CL）对其发育和退化至关重要。从非灵长类物种获得的证据 表明前列腺素（PG）调节黄体结构功能，但它们在灵长类黄体生理学中的作用 尚未定义。最近的初步数据表明，PGE2 合成的表达 （前列腺素内过氧化物合酶 2 或 PTGS2；微粒体 PGE2 合酶-1 或 PTGES）和信号转导 (PGE2 受体 3 或 PTGER3) 成分在恒河猴 CL 中达到峰值 发展。此外，PGE2 合成和信号传导成分的表达显着 在 CL 功能退化之前下降，这也与水平增加同时发生 PGF2_受体(PTGFR)表达的影响。因此，将进行实验来检验 PGE2 的假设 作用对于灵长类黄体发育至关重要，而 PGF2_ 作为关键的黄体内启动子和/或 黄体溶解的效应器。提议使用恒河猴进行研究，以评估 PGE2 信号传导的作用 在灵长类 CL 的发育中发挥作用（目标 1），并评估 PGF2_ 信号传导是否是必需的 CL 在黄体期结束时死亡（目标 2）。通过a阻断黄体内PG合成的方案 PTGS2 选择性抑制剂将决定其在 CL 发展中的作用。 PG合成的消融 开发 CL 将与通过使用选择性的 PTGER3 信号恢复相结合 PTGER3 激动剂。在黄体退化开始之前，在黄体内注射 PTGFR 拮抗剂将 确定 PGF2_ 在黄体溶解中的作用。月经第一天的每日血清孕酮浓度，以及 CL 重量将用于评估黄体功能和寿命。细胞凋亡的组织化学标记， 内皮细胞和类固醇生成细胞将用于 CL 结构的形态学分析，而表达 LH 调节的类固醇生成和血管生成因子的数量将被量化，以评估之间的关系 PG 信号传导和黄体功能。这些研究将为 PG 作用在黄体中的作用提供新的见解。 灵长类动物的发育和退化。这样理解PG参与黄体的调节 结构功能可能有助于我们了解不孕症或与黄体相关的其他疾病 功能障碍。