Retinoic acid signaling in decidualization

蜕膜化中的视黄酸信号传导

基本信息

批准号：
10280145
负责人：
Liang Ma
金额：
$ 33.86万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10280145
关键词：
Abnormal placentation Biology Birth Cell Communication Cell model Cells Conceptus Contraceptive Agents Data Decidual Cell Decidual Cell Reactions Defect Development Dominant-Negative Mutation Endometrial Stromal Cell Epithelial Exhibits Failure Fertilization in Vitro Fetal Growth Fibroblast Growth Factor Fibroblasts Gene Expression Profiling Gene Proteins Gene Silencing Genes Genetic Genetic Transcription Growth Factor Homeodomain Proteins Human Implant Infertility Knock-out Knockout Mice Lead Limb Development LoxP-flanked allele Mediating Mus Mutant Strains Mice Pathway interactions Phenotype Pregnancy Procedures Process Progesterone Prolactin Regulator Genes Reporting Reproduction Retinoic Acid Receptor Screening procedure Signal Pathway Signal Transduction Small Interfering RNA System Technology Tissues Tretinoin Uterus adverse pregnancy outcome base conditional knockout drug discovery endometriosis failure Implantation female fertility follow-up gene synthesis genome-wide high throughput screening hormonal signals human embryonic stem cell implantation improved loss of function mouse model natural Blastocyst Implantation novel pregnancy failure promoter response screening success tool transcriptome sequencing whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Human infertility is a global problem and failure of embryo implantation accounts for a significant percentage of pregnancy failure during both natural pregnancy and in vitro fertilization procedures. Implantation is an extremely complicated process requiring precisely controlled hormone signaling, growth factor signaling, and cell-cell interactions. Decidualization is a required step in the implantation process. It involves the rapid proliferation and differentiation of fibroblast-like endometrial stromal cells into epitheloid-like decidual cells. These cells become part of the decidual tissue that surrounds the implanting conceptus. Decidualization defects can directly lead to implantation failure. Moreover, early decidualization defects can cause other adverse pregnancy outcomes including abnormal placentation, restricted intrauterine fetal growth, and early parturition. Understanding decidualization is crucial for improving IVF success rates, developing novel contraceptives, and discovering new treatments for endometriosis. Despite its significance in reproduction, the genetic framework of decidualization had never been systematically studied until our recent development of a suitable high throughput screening tool, immortalized human endometrial stromal cells that carry the yellow fluorescent protein gene under the control of the progesterone-sensitive prolactin promoter (PRL-Y cells). We recently used PRL-Y cells to perform a whole genome siRNA functional screen to uncover novel regulatory genes for human decidualization. One major signaling pathway uncovered by the screen is the retinoic acid (RA) signaling pathway. Contrary to the current dogma that RA suppresses decidualization, we propose a paradigm-shifting hypothesis that RA signaling is absolutely required to initiate and promote decidualization, and is therefore required for female fertility. In this proposal, we will follow up on our exciting preliminary findings and study the function of RA signaling during decidualization through careful mapping of its downstream signaling pathways. In Aim I we will determine which RAR or combination of RARs is required during decidualization, and we will clarify the tissue-specific requirements for RA signaling during peri-implantation. In Aim II, we will identify RA downstream targets during decidualization in mouse and human. Finally in Aim III, we will investigate the interplay between RA and FGF signaling, and between RA and homeodomain proteins during decidualization. Successful completion of this project will dramatically increase our understanding of RA signaling during implantation/decidualization and will have an enduring impact on implantation biology and drug discovery.

项目概要/摘要人类不孕症是一个全球性问题，胚胎植入失败是一个重要原因自然妊娠和体外受精过程中妊娠失败的百分比。着床是一个极其复杂的过程，需要精确控制的激素信号传导，生长因子信号传导和细胞间相互作用。蜕膜化是着床的必要步骤过程。它涉及成纤维细胞样子宫内膜基质细胞的快速增殖和分化进入类上皮样蜕膜细胞。这些细胞成为周围蜕膜组织的一部分植入孕体。蜕膜化缺陷可直接导致着床失败。而且，早蜕膜化缺陷可能导致其他不良妊娠结局，包括胎盘异常、宫内胎儿生长受限，早产。了解蜕膜化对于提高体外受精的成功率，开发新型避孕药，并发现新的治疗方法子宫内膜异位症。尽管在繁殖中具有重要意义，但蜕膜化的遗传框架直到我们最近开发出合适的高通量筛选方法之前，从未对其进行过系统研究工具，携带黄色荧光蛋白基因的永生化人子宫内膜基质细胞黄体酮敏感催乳素启动子（PRL-Y 细胞）的控制。我们最近使用了PRL-Y 细胞进行全基因组 siRNA 功能筛选，以发现人类新的调控基因蜕膜化。屏幕发现的一个主要信号通路是视黄酸 (RA) 信号通路。与当前 RA 抑制蜕膜化的教条相反，我们提出了一种范式转换假设，即 RA 信号传导绝对需要启动和促进蜕膜化，因此是女性生育能力所必需的。在此提案中，我们将跟进我们的令人兴奋的初步发现并通过以下方式研究 RA 信号在蜕膜化过程中的功能仔细绘制其下游信号通路。在目标 I 中，我们将确定哪个 RAR 或蜕膜化过程中需要结合RAR，我们将阐明组织特异性植入期间 RA 信号传导的要求。在目标 II 中，我们将确定 RA 下游目标在小鼠和人类的蜕膜化过程中。最后，在目标 III 中，我们将研究之间的相互作用 RA 和 FGF 信号传导，以及蜕膜化过程中 RA 和同源域蛋白之间的信号传导。成功的该项目的完成将极大地增加我们对 RA 信号传导的理解着床/蜕膜化将对着床生物学和药物产生持久影响发现。