Molecular mechanism of LPA3-mediated uterine receptivity

LPA3介导的子宫容受性的分子机制

• 批准号: 8711523
• 负责人: Xiaoqin Ye
• 金额: $ 30.67万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711523
• 关键词: Biological Assay; Cells; Data; Diagnostic; Down-Regulation; Economic Burden; Embryo; Emotional; Endometrium; Epithelium; Failure; Foundations; G-Protein-Coupled Receptors; Gene Targeting; Genes; Goals; Hormonal; Human; Immunoblotting; Implant; Infertility; Knowledge; Lasers; Lysophosphatidic Acid Receptors; Lysophospholipids; Mammals; Mediating; Microdissection; Molecular; Mus; Outcome; Pathway interactions; Patients; Pattern; Pregnancy loss; Progesterone; Progesterone Receptors; Public Health; Receptor Signaling; Research; Right-On; Role; Signal Transduction; Therapeutic; Uterus; Woman; Work; base; drug discovery; endometriosis; implantation; insight; lysophosphatidic acid; natural Blastocyst Implantation; preimplantation; receptor expression; reproductive; spatiotemporal; uterine receptivity

DESCRIPTION (provided by applicant): Defective uterine receptivity, including delayed uterine receptivity and non-receptive endometrium, is the key maternal factor for infertility and early pregnancy loss. The molecular mechanism of how a uterus transforms into a receptive state for embryo implantation is not well understood. It is well recognized that progesterone receptor (PR)-mediated hormonal signaling is essential for the establishment of uterine receptivity in all mammals studied. PR has dynamic spatiotemporal expression patterns in the peri-implantation uterus. The disappearance of PR from uterine luminal (LE) and glandular epithelium is associated with the establishment of uterine receptivity. Failure of such down regulation of PR in uterine epithelium during the expected "implantation window" is associated with defective uterine receptivity. LPA3 (LPAR3/EDG7) is the third receptor for lysophosphatidic acid. Down regulation of uterine LPA3 is implicated in defective uterine receptivity in endometriosis patients and deletion of Lpar3 in mice leads to delayed uterine receptivity. Sustained PR expression in LE is detected in the non-receptive day 4.5 Lpar3(-/-) mouse uterus (normal implantation: ~day 4.0 in mouse). How the sustained PR expression in LE during the expected "implantation window" blocks uterine receptivity and how PR-mediated hormonal signaling interacts with local targets to control uterine receptivity remain as significant knowledge gaps. The long-term goal is to understand the molecular mechanism of uterine receptivity thus help overcome infertility and early pregnancy loss associated with defective uterine receptivity. The overall objective of this application is to fill the mentioned knowledge gaps, specifically the significance of sustained PR expression in LE and the interplay between PR and LPA3 in LE. The central hypothesis, formulated based on supportive preliminary data, is that PR interplays with LPA3 to coordinately regulate uterine receptivity. The rationale is that understanding the significance of PR in LE and its interplay with LPA3 will provide more insight into the molecular mechanism of uterine receptivity. To achieve the goal of this application, three specific aims will be pursed. Aim 1. Determine molecular pathways dysregulated in LE with sustained PR expression, based on the working hypothesis that sustained PR expression in LE dysregulates genes/molecular pathways leading to a non-receptive uterus. Aim 2. Determine interplay between PR and LPA3 in LE, based on the working hypo- thesis that PR and LPA3 mutually regulate each other in LE for the establishment of uterine receptivity. Aim 3. Determine role of LPA3 in regulating molecular pathways in preimplantation day 3. 5 endometrium, based on the working hypothesis that LPA3 regulates its uterine target genes to influence uterine receptivity directly and/or via PR in LE. Laser microdissection, gene profiling, immunoblotting, ChIP assay, and immonoprecipitation are among the approaches that will be employed. The proposed work is significant because understanding the molecular mechanism of uterine receptivity is critical for developing diagnostic and therapeutic approaches to detect and treat infertility and early pregnancy loss associated with defective uterine receptivity.

描述（申请人提供）：子宫容受性缺陷，包括子宫容受性延迟和子宫内膜非容受性，是导致不孕和早期流产的关键母体因素。子宫如何转变为胚胎植入接受状态的分子机制尚不清楚。众所周知，黄体酮受体（PR）介导的激素信号传导对于所有研究的哺乳动物子宫容受性的建立至关重要。 PR 在围着床子宫中具有动态时空表达模式。 PR 从子宫腔 (LE) 和腺上皮的消失与子宫容受性的建立相关。在预期的“着床窗口”期间，子宫上皮细胞中 PR 的下调失败与子宫容受性缺陷有关。 LPA3 (LPAR3/EDG7) 是溶血磷脂酸的第三个受体。 子宫 LPA3 的下调与子宫内膜异位症患者的子宫容受性缺陷有关，而小鼠 Lpar3 的缺失会导致子宫容受性延迟。在非接受第 4.5 天 Lpar3(-/-) 小鼠子宫中检测到 LE 中持续的 PR 表达（正常植入：约第 4.0 天小鼠）。在预期的“着床窗口”期间，LE 中持续的 PR 表达如何阻碍子宫容受性，以及 PR 介导的激素信号如何与局部靶标相互作用以控制子宫容受性仍然是重大的知识差距。长期目标是了解子宫容受性的分子机制，从而帮助克服与子宫容受性缺陷相关的不孕症和早期妊娠流产。本申请的总体目标是填补上述知识空白，特别是 LE 中持续 PR 表达的重要性以及 LE 中 PR 和 LPA3 之间的相互作用。基于支持性初步数据制定的中心假设是 PR 与 LPA3 相互作用以协调调节子宫容受性。其基本原理是，了解 PR 在 LE 中的重要性及其与 LPA3 的相互作用将有助于更深入地了解子宫容受性的分子机制。为了实现该应用程序的目标，将追求三个具体目标。目标 1. 基于 LE 中持续 PR 表达失调导致非容受性子宫的基因/分子途径失调的工作假设，确定 LE 中持续 PR 表达失调的分子途径。目标 2. 基于 PR 和 LPA3 在 LE 中相互调节以建立子宫容受性的工作假设，确定 LE 中 PR 和 LPA3 之间的相互作用。目标 3. 基于 LPA3 调节其子宫靶基因直接和/或通过 LE 中的 PR 影响子宫容受性的工作假设，确定 LPA3 在调节着床前第 3. 5 天子宫内膜分子途径中的作用。将采用的方法包括激光显微切割、基因分析、免疫印迹、ChIP 测定和免疫沉淀。这项工作意义重大，因为了解子宫容受性的分子机制对于开发诊断和治疗方法来检测和治疗与子宫容受性缺陷相关的不孕症和早孕流产至关重要。