PROSTAGLANDIN SIGNALING IN FEMALE REPRODUCTION

描述（改编自申请人的描述）：环氧合酶 （考克斯）衍生的PG涉及生殖的许多方面，包括 排卵、着床和分娩，但信息有限 关于子宫中PG配体-受体信号的调节。 这 申请将为主要研究者（PI）提供平衡的 教育和研究计划，以调查PG信号的机制， 在一位成熟的生殖科学家的指导下， 的 建议得到了具有分娩和PG专业知识的顾问的支持 生物学 早产仍然是一个令人困惑的临床问题，尽管努力 识别和治疗早产的根本原因。 申请人 检查小鼠的分娩，以更好地了解 这个过程 初步结果表明：1）考克斯-1在人乳腺癌组织中有明显表达 和考克斯-2发生在足月子宫; 2）雌激素和孕激素受体 分别共定位于考克斯-1和考克斯-2表达的特异位点; 3)考克斯-2衍生的PG不能补偿考克斯-1-/-中的分娩失败 小鼠，尽管外源性PG是有效的;和4）胎儿PG拯救 携带野生型胚胎的考克斯-1 -/-受体小鼠的分娩失败 胚胎移植的结果。 总的来说，这些结果表明， 分娩的多个方面集中在PG信号通路上。 的 卵巢类固醇激素的作用和卵巢激素受体的信号， 分娩定义不明确。 因此，一种分娩模型， 包括这些配体和受体的关系。 本申请的目的是确定PG的细胞来源 和它们的受体，检查卵巢类固醇对它们的影响。 表达，并确定胎儿PG的贡献，分娩中， 老鼠. 核心假设是雌激素和孕激素发挥作用， 通过改变PG配体水平对分娩产生显著影响，或 受体，以及子宫收缩力和宫颈成熟在任期内 和早产是由不同的PG的差异作用介导的 受体。 申请人将使用遗传学和药理学方法： 1)检查PG合成的来源和类固醇调节， 早产; 2）确定PG在足月或早产时的作用部位 分娩; 3）量化胎儿和胎盘来源的PG对足月妊娠的贡献 和早产;和4）确定早产是否发生在 PG缺陷小鼠，以及这是否是由不同的途径调节，而不是在 野生型小鼠。 本研究将使用考克斯-1-/-和cPLA 2-/-小鼠，选择性考克斯 抑制剂，以及已建立的诱导早产的方法。 的 这些实验的结果将加强对母胎的理解， PG信号，并可能提供新的见解过早或 女性功能失调的分娩。

DESCRIPTION (Adapted from the applicant's description): Cyclooxygenase (COX)-derived PGs are implicated in many aspects of reproduction, including ovulation, implantation and parturition, yet limited information is available regarding the regulation of PG ligand-receptor signaling in the uterus. This application will provide the principal investigator (PI) with a balanced educational and research program to investigate mechanisms of PG signaling in the mouse under the mentorship of an established reproductive scientist. The proposal is supported by advisors with expertise in parturition and PG biology. Premature birth remains a perplexing clinical problem despite efforts to identify and treat the underlying causes of preterm labor. The applicant is examining parturition in the mouse to better understand the molecular basis of this process. Preliminary results show that: 1) distinct expression of COX-1 and COX-2 occurs in the term uterus; 2) estrogen and progesterone receptors co-localize to the specific sites of COX-1 and COX-2 expression, respectively; 3) COX-2-derived PGs do not compensate for parturition failure in COX-1-/- mice, although exogenous PGs are effective; and 4) fetal PGs rescue parturition failure in COX-1 -/- recipient mice carrying wild-type embryos resulting from embryo transfer. Collectively, these results suggest that multiple aspects of parturition converge on the PG signaling pathway. The effects of ovarian steroids and the receptors that transduce PG signals during parturition are poorly defined. Thus, a model for parturition that encompasses these ligand and receptor relationships is needed. The objective of this application is to identify the cellular source of PGs and their receptors, examine the influence of ovarian steroids on their expression, and determine the contribution of fetal PGs to parturition in the mouse. The central hypothesis is that estrogen and progesterone exert significant effects on parturition by altering the levels of PG ligands or receptors, and that uterine contractility and cervical maturation during term and preterm labor are mediated by the differential actions of distinct PG receptors. The applicant will use genetic and pharmacologic approaches to: 1) examine the source and steroid regulation of PG synthesis during term or preterm labor; 2) determine the sites of PG actions during term or preterm labor; 3) quantify the contribution of fetal and placental-derived PGs to term and preterm labor; and 4) determine whether preterm labor occurs in PG-deficient mice and whether this is regulated by different pathways than in wild-type mice. The study will use COX-1-/- and cPLA2-/- mice, selective COX inhibitors, and an established method for induction of preterm labor. The results of these experiments will enhance the understanding of maternal-fetal PG signaling, and are likely to provide new insights into premature or dysfunctional labor in women.