Prostaglandin Synthesis and Action in the Primate Corpus Luteum

项目主任/首席调查员(最后、第一、中间)：亨尼博尔德，乔恩 PHS 398/2590(11/07版)页面续格式页面 摘要 这项研究的长期目标是确定灵长类语料库中发生的机制 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 提示前列腺素(PGs)调节黄体结构和功能，但它们在灵长类黄体生理中的作用 还没有被定义。最近的初步数据表明，PGE2合成的表达 (前列腺素-过氧化物合成酶2或Ptgs2；微粒体PGE2合成酶-1或PTGES)与信号转导 (PGE2受体3或PTGER3)成分在恒河猴CL的整个发育期达到高峰 发展。此外，PGE2合成和信号转导组分的表达显著 在CL功能退化期之前下降，这也与上升水平相一致 前列腺素F2受体(PTGFR)的表达。因此，将进行实验来检验PGE2的假设 活动对灵长类黄体发育至关重要，而PGF2_2则是黄体内的关键启动子和/或 黄体溶解的效应物。使用恒河猴进行的研究将评估PGE2信号的作用 在灵长类CL的发育中发挥作用(目标1)，并评估是否需要PGF2信号转导 黄体期结束时CL消亡(目标2)。阻止黄体内PG合成的方案 Ptgs2选择性抑制物将决定它们在CL发生中的作用。PG合成的烧蚀 发展CL将与恢复PTGER3信号相结合，通过使用选择性的 PTGER3激动剂。在黄体退化开始之前，黄体内注射PTGFR拮抗剂将 确定PGF2在黄体溶解中的作用。每日血清孕酮浓度，月经第一天，和 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志物， 内皮细胞和类固醇生成细胞将用于CL结构的形态分析，而表达 将黄体生成素调节的类固醇生成因子和血管生成因子进行量化，以评价二者之间的关系 PG信号与黄体功能。这些研究将为PG在黄体中的作用提供新的见解 灵长类动物的发育和退化。对PG参与黄体调节的认识 结构功能可能有助于我们对不孕症或其他与黄体有关的疾病的了解。 功能障碍。

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.