Molecular mechanism of LPA3-mediated uterine receptivity

LPA3介导的子宫容受性的分子机制

• 批准号: 8050258
• 负责人: Xiaoqin Ye
• 金额: $ 31.56万
• 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/8050258
• 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because defective uterine receptivity is a key factor for two important public health problems, infertility and early pregnancy loss. This proposal aims to decipher how a local factor LPA3 interplays with progesterone receptor in uterine luminal epithelium to control uterine receptivity. The understanding of the molecular mechanism in establishment of uterine receptivity will provide the foundation for drug discoveries to treat infertility and early pregnancy loss associated with defective uterine receptivity.

描述（由申请人提供）：子宫容受性缺陷，包括子宫容受性延迟和非容受性子宫内膜，是不孕和早孕丢失的关键母体因素。子宫如何转变为胚胎植入的接受状态的分子机制还没有很好的理解。众所周知，孕激素受体（PR）介导的激素信号是必不可少的建立子宫容受性在所有哺乳动物的研究。PR在围着床期子宫中具有动态的时空表达模式。PR从子宫腔（LE）和腺上皮的消失与子宫容受性的建立有关。在预期的“着床窗”期间，子宫上皮中PR的这种下调失败与子宫容受性缺陷有关。LPA 3（LPAR 3/EDG 7）是溶血磷脂酸的第三种受体。 子宫LPA 3的下调与子宫内膜异位症患者的子宫容受性缺陷有关，小鼠中Lpar 3的缺失导致子宫容受性延迟。在非接受性第4.5天Lpar 3（-/-）小鼠子宫中检测到LE中的持续PR表达（正常着床：小鼠中约第4.0天）。在预期的“着床窗口”期间LE中持续的PR表达如何阻断子宫容受性以及PR介导的激素信号传导如何与局部靶点相互作用以控制子宫容受性仍然是重要的知识空白。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丢失。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表达的意义以及LE中PR和LPA 3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LPA 3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中的意义及其与LPA 3的相互作用将为子宫容受性的分子机制提供更多的见解。为了实现本申请的目标，将追求三个具体目标。目标1.基于LE中持续PR表达失调基因/分子途径导致非接受性子宫的工作假设，确定LE中持续PR表达失调的分子途径。目标二。基于PR和LPA 3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LPA 3之间的相互作用。目标3.确定LPA 3在着床前第3天调节分子通路中的作用。5子宫内膜，基于LPA 3调节其子宫靶基因以直接和/或通过LE中的PR影响子宫容受性的工作假设。激光显微切割，基因分析，免疫印迹，ChIP测定和免疫沉淀是其中的方法，将采用。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以检测和治疗与子宫容受性缺陷相关的不孕症和早期妊娠丢失至关重要。 公共卫生关系：拟议的研究与公共卫生有关，因为子宫容受性缺陷是不孕症和早孕流产这两个重要公共卫生问题的关键因素。本研究旨在阐明局部因子LPA 3如何与子宫腔上皮中的孕酮受体相互作用以控制子宫容受性。对子宫容受性建立的分子机制的理解将为药物发现提供基础，以治疗与子宫容受性缺陷相关的不孕症和早期妊娠丢失。