Luminal epithelial microenvironment in Lpar3(-/-) peri-implantation uterus

Lpar3(-/-)围着床子宫的管腔上皮微环境

• 批准号: 7980380
• 负责人: Xiaoqin Ye
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7980380
• 关键词: Appearance; Biological Assay; Candidate Disease Gene; Cells; Chemistry; Cytolysis; Data; Diagnostic; Down-Regulation; Economic Burden; Embryo; Emotional; Endometrial; Ensure; Environment; Epithelial; Epithelium; Event; Extracellular Matrix; Foundations; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Histology; Implant; Infertility; Knowledge; Lead; Lysophosphatidic Acid Receptors; Lysophospholipids; Mediating; Messenger RNA; Molecular; Mus; Outcome; Ovarian hormone; Patients; Pregnancy loss; Public Health; Research; Role; Scanning Transmission Electron Microscopy Procedures; Signal Transduction; Therapeutic; Uterus; Woman; Work; base; drug discovery; endometriosis; experience; implantation; innovation; insight; lysophosphatidic acid; mouse model; preimplantation; promoter; public health relevance; reproductive; uterine receptivity

DESCRIPTION (provided by applicant): Uterine receptivity is an ovarian hormone controlled transient state in which the uterus can accept an embryo to implant. Transformations in luminal endometrial epithelium (LE) mi- croenvironment are associated with the establishment of uterine receptivity. Dysregulated LE microenvironment during implantation window is implicated in defective uterine receptivity. A fundamental knowledge gap is what and how local factors mediate ovarian hormone signals to transform LE microenvironment upon the establishment of uterine receptivity. LPAR3, the third receptor for lysophosphatidic acid (LPA) implicated in uterine receptivity, is mainly ex- pressed in LE and deletion of Lpar3 leads to altered expression of genes involved in regulat-ing LE microenvironment in preimplantation day 3.5 uterus. Our long-term goal is to under- stand the molecular mechanism of uterine receptivity. The overall objective of this application, which is a step toward attaining our long-term goal, is to identify altered LE microenvironment and associated candidate genes in the Lpar3(-/-) uterus. The central hypothesis is that LPAR3 is a local factor regulating LE microenvironment via gene expression. This hypothesis is for- mulated based on our preliminary data obtained from Lpar3(-/-) mice. The rationale is that un- derstanding the role of LPAR3 in LE microenvironment will give us more insight into the mo- lecular mechanism of uterine receptivity. To achieve the goal of this application, two specific aims will be pursed. Aim 1. Identify altered LE microenvironment in peri-implantation Lpar3(-/-) uterus, based on the working hypothesis that deletion of Lpar3 leads to an unfavorable LE microenvironment for implantation. Aim 2. Determine expression of candidate genes asso- ciated with the altered LE microenvironment in peri-implantation Lpar3(-/-) LE, based on the working hypothesis that altered LE microenvironment is caused by altered gene transcription in Lpar3(-/-) LE. Scanning and transmission electron microscopy, realtime PCR, promoter ana- lyses, ChIP assay, and pharmacological approaches will be employed. The proposed re- search is significant because it is expected to decipher the molecular mechanism of how local factor LPAR3 regulates the expression of genes that can influence LE microenvironment thus uterine receptivity. The obtained knowledge will advance and expand our understanding of the molecular mechanism of uterine receptivity. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because defective uterine receptivity is a key factor for infertility and early pregnancy loss. This proposal aims to understand how LPAR3 regulates the expression of genes involved in the transformations of luminal endome- trial epithelium microenvironment to influence uterine receptivity. The understanding of the molecular mechanism in establishment of uterine receptivity will provide a foundation for drug discoveries to treat infertility and early pregnancy loss associated with defective uterine re- ceptivity.

描述（由申请人提供）：子宫容受性是一种卵巢激素控制的短暂状态，在这种状态下，子宫可以接受胚胎植入。子宫内膜腔上皮（LE）微环境的改变与子宫容受性的建立有关。着床窗口期LE微环境失调与子宫容受性缺陷有关一个基本的知识缺口是什么以及如何局部因素介导卵巢激素信号转化LE微环境后，建立子宫容受性。LPAR 3是溶血磷脂酸（LPA）的第三种受体，主要在LE中表达，LPAR 3的缺失导致着床前3.5天子宫LE微环境调控基因表达改变。我们的长期目标是了解子宫容受性的分子机制。本申请的总体目标是鉴定Lpar 3（-/-）子宫中改变的LE微环境和相关候选基因，这是实现我们长期目标的一步。中心假设是LPAR 3是通过基因表达调节LE微环境的局部因子。这一假设是基于我们从Lpar 3（-/-）小鼠获得的初步数据而得出的。其基本原理是，了解LPAR 3在LE微环境中的作用将使我们更深入地了解子宫容受性的分子机制。为了实现本申请的目标，将追求两个具体目标。目标1.基于Lpar 3缺失导致对着床不利的LE微环境的工作假设，鉴定围着床期Lpar 3（-/-）子宫中改变的LE微环境。目标二。基于LE微环境改变是由Lpar 3（-/-）LE中基因转录改变引起的工作假设，确定与植入期Lpar 3（-/-）LE中LE微环境改变相关的候选基因表达。将采用扫描和透射电子显微镜、实时PCR、启动子分析、ChIP测定和药理学方法。该研究具有重要意义，因为它有望解释局部因子LPAR 3如何调节基因表达的分子机制，这些基因可以影响LE微环境，从而影响子宫容受性。所获得的知识将推进和扩大我们对子宫容受性的分子机制的理解。 公共卫生关系：这项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的关键因素。本研究旨在了解LPAR 3是如何调节参与子宫内膜微环境转化的基因表达从而影响子宫容受性的。对子宫容受性建立的分子机制的理解将为治疗与子宫容受性缺陷相关的不孕症和早期妊娠丢失的药物发现提供基础。