PROSTAGLANDIN SIGNALING IN FEMALE REPRODUCTION

女性生殖中的前列腺素信号传导

基本信息

批准号：
6879057
负责人：
John Jeffrey Reese
金额：
$ 12.6万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-04 至 2007-04-30
项目状态：
已结题

项目摘要

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.

描述（改编自申请人的描述）：环加氧酶 (COX) 衍生的 PG 涉及生殖的许多方面，包括排卵、着床和分娩，但可获得的信息有限关于子宫内 PG 配体受体信号传导的调节。这应用程序将为主要研究者（PI）提供平衡的研究 PG 信号传导机制的教育和研究计划在一位知名生殖科学家的指导下的老鼠。这提案得到了具有分娩和 PG 专业知识的顾问的支持生物学。尽管做出了努力，早产仍然是一个令人困惑的临床问题识别并治疗早产的根本原因。申请人是检查小鼠的分娩以更好地了解分娩的分子基础这个过程。初步结果表明：1）COX-1的明显表达 COX-2 出现在足月子宫中； 2）雌激素和孕激素受体分别共定位于 COX-1 和 COX-2 表达的特定位点； 3) COX-2 衍生的 PG 不能补偿 COX-1-/- 的分娩失败小鼠，尽管外源性 PG 有效； 4) 胎儿 PG 救援携带野生型胚胎的 COX-1 -/- 受体小鼠分娩失败由胚胎移植产生。总的来说，这些结果表明分娩的多个方面都集中在 PG 信号通路上。这卵巢类固醇和转导 PG 信号的受体的作用分娩的定义不明确。因此，分娩模型需要涵盖这些配体和受体的关系。此应用的目的是确定 PG 的细胞来源及其受体，检查卵巢类固醇对其的影响表达，并确定胎儿 PG 对分娩的贡献老鼠。中心假设是雌激素和孕激素发挥作用通过改变 PG 配体的水平对分娩产生显着影响或受体，以及足月期间的子宫收缩力和宫颈成熟和早产是由不同 PG 的不同作用介导的受体。申请人将使用遗传和药理学方法来： 1) 检查足月期间 PG 合成的来源和类固醇调节早产； 2) 确定足月或早产期间PG作用的部位劳动; 3) 量化胎儿和胎盘来源的 PG 对足月的贡献和早产； 4) 确定是否发生早产 PG 缺陷小鼠以及这是否受到与正常小鼠不同的途径的调节野生型小鼠。该研究将使用 COX-1-/- 和 cPLA2-/- 小鼠，选择性 COX 抑制剂，以及引产早产的既定方法。这这些实验的结果将加深对母胎关系的理解 PG 信号传导，并可能为过早或过早的疾病提供新的见解女性分娩功能障碍。