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）：子宫容受性是卵巢激素控制的瞬时状态，在该状态下子宫可以接受胚胎植入。子宫内膜上皮（LE）微环境的转变与子宫容受性的建立相关。着床窗口期间 LE 微环境失调与子宫容受性缺陷有关。一个基本的知识差距是局部因素是什么以及如何介导卵巢激素信号，从而在子宫容受性建立后改变 LE 微环境。 LPAR3 是与子宫容受性有关的溶血磷脂酸 (LPA) 的第三种受体，主要在 LE 中表达，Lpar3 的缺失会导致植入前第 3.5 天子宫中参与调节 LE 微环境的基因表达改变。我们的长期目标是了解子宫容受性的分子机制。该应用的总体目标是识别 Lpar3(-/-) 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 LPAR3 是通过基因表达调节 LE 微环境的局部因子。这一假设是根据我们从 Lpar3(-/-) 小鼠获得的初步数据提出的。其基本原理是，了解 LPAR3 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。为了实现该应用程序的目标，将追求两个具体目标。目标 1. 基于 Lpar3 缺失会导致不利于植入的 LE 微环境这一工作假设，识别围着床 Lpar3(-/-) 子宫中改变的 LE 微环境。目标 2. 确定与植入周围 Lpar3(-/-) LE 中 LE 微环境改变相关的候选基因的表达，基于改变 LE 微环境是由 Lpar3(-/-) 基因转录改变引起的工作假设LE。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。这项研究意义重大，因为它有望破译局部因子 LPAR3 如何调节影响 LE 微环境从而影响子宫容受性的基因表达的分子机制。所获得的知识将推进和扩大我们对子宫容受性分子机制的理解。 公共健康相关性：拟议的研究与公共健康相关，因为子宫容受性缺陷是不孕和早期妊娠流产的关键因素。本提案旨在了解 LPAR3 如何调节参与子宫内膜上皮微环境转变的基因表达，从而影响子宫容受性。了解子宫容受性建立的分子机制将为开发治疗与子宫容受性缺陷相关的不孕症和早孕流产的药物奠定基础。