Prostaglandin Synthesis and Action in the Primate Corpus Luteum

项目主任/主要研究者（最后，第一，中间）：Hennebold，Jon PHS 398/2590（Rev. 11/07） 摘要 本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）是其发展和退化的关键。从非灵长类物种中获得的证据 表明，洋地黄素（PGs）调节黄体结构-功能，但它们在灵长类动物黄体生理中的作用， 尚未定义。最近的初步数据表明，PGE 2合成的表达 （洋地黄素-内过氧化物合酶2或PTGS 2;微粒体PGE 2合酶-1或PTGES）和信号传导 (PGE2受体3或PTGER 3）成分在恒河猴CL中通过其 发展此外，PGE 2合成和信号传导组分的表达显著增加， 在CL的功能消退期之前降低，这也与CL水平的增加相一致。 前列腺素F_（2_）受体（PTGFR）的表达。因此，将进行实验以检验PGE 2 行动是至关重要的灵长类动物黄体发育，而PGF 2_作为一个关键的黄体内引发剂和/或 黄体溶解效应子。建议使用恒河猴进行研究，以评估PGE 2信号传导的作用 在灵长类CL的发育中起作用（目的1），并评估PGF 2_信号传导是否是灵长类CL发育所需的。 在黄体期结束时CL死亡（目标2）。阻断输卵管内PG合成的方案 PTGS 2选择性抑制剂将决定其在CL发展中的作用。切除前列腺素的合成 发展CL将与通过使用选择性免疫抑制剂恢复PTGER 3信号传导相结合。 PTGER 3激动剂。在黄体退化开始前，黄体内给予PTGFR拮抗剂， 探讨PGF_（2-）在黄体溶解中的作用。每日血清孕酮浓度，月经第一天， CL重量将用于评价黄体功能和寿命。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调节的类固醇生成因子和血管生成因子将被量化，以评估 PG信号和黄体功能。这些研究将提供新的见解PG行动的作用，在黄体 灵长类动物的发育和退化这种对PG参与调节黄体功能的理解， 结构-功能可能有助于我们了解不孕症或其他与黄体功能相关的疾病。 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.