Retinoic acid signaling in decidualization

项目摘要/摘要 人类不孕不育是一个全球性的问题，胚胎植入失败是一个重要的原因 自然妊娠和体外受精过程中的妊娠失败率。 植入是一个极其复杂的过程，需要精确控制的激素信号， 生长因子信号和细胞间的相互作用。蜕膜化是植入过程中的必要步骤。 进程。它涉及成纤维细胞样子宫内膜间质细胞的快速增殖和分化 转化为类上皮样蜕膜细胞。这些细胞成为围绕着子宫内膜的蜕膜组织的一部分 植入胚胎。蜕膜化缺陷可直接导致植入失败。此外，早些时候 蜕膜化缺陷会导致其他不良妊娠结局，包括胎盘异常， 胎儿宫内发育受限，早产。理解蜕膜化对于 提高试管受精成功率，开发新的避孕药，并发现新的治疗方法 子宫内膜异位症。尽管蜕膜化在生殖中具有重要意义，但它的遗传框架 直到我们最近开发出一种合适的高通量筛选方法，才对其进行了系统的研究 工具，永生化携带黄色荧光蛋白基因的人子宫内膜间质细胞 孕酮敏感的催乳素启动子(PRL-Y细胞)的调控。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。筛选发现的一个主要信号通路是维甲酸(RA)。 信号通路。与目前认为RA抑制去女性化的教条相反，我们提出了一种 范式转换假说：RA信号绝对需要启动和促进 蜕膜化，因此是女性生育所必需的。在这项提案中，我们将跟进我们的 激动人心的初步发现并研究RA信号在蜕膜形成过程中的作用 仔细绘制其下游信号通路。在AIM I中，我们将确定哪个RAR或 在蜕膜化过程中需要联合使用RARs，我们将阐明组织特异性 植入围术期RA信号的要求。在AIM II中，我们将确定RA下游目标 在小鼠和人类蜕膜化过程中。最后，在AIM III中，我们将研究 RA和成纤维细胞生长因子信号转导，以及蜕膜化过程中RA和同源结构域蛋白之间的信号转导。成功 该项目的完成将极大地增加我们对RA信令的了解 植入/蜕膜化，将对植入生物学和药物产生持久的影响 发现号。

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.