Retinoic acid signaling in decidualization

项目总结/摘要 人类不育是一个全球性的问题，胚胎植入失败是导致人类不育的重要原因。 自然妊娠和体外受精过程中妊娠失败的百分比。 植入是一个非常复杂的过程，需要精确控制激素信号， 生长因子信号传导和细胞-细胞相互作用。蜕膜化是着床的必要步骤 过程它涉及子宫内膜间质细胞的快速增殖和分化 上皮样蜕膜细胞。这些细胞成为蜕膜组织的一部分， 着床蜕膜化缺陷可直接导致着床失败。此外，早 蜕膜化缺陷可引起其它不良妊娠结果包括异常胎盘形成， 胎儿宫内生长受限，早产。了解蜕膜化对于 提高IVF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其在生殖中的重要性，遗传框架的蜕膜化， 直到我们最近开发出一种合适的高通量筛选方法， 工具，永生化人子宫内膜基质细胞，携带黄色荧光蛋白基因， 对孕酮敏感的催乳素启动子（PRL-Y细胞）的控制。我们最近使用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， 蜕膜化通过筛选发现的一个主要信号通路是视黄酸（RA） 信号通路与目前RA抑制蜕膜化的教条相反，我们提出了一个新的观点， 范式转移假说，RA信号是绝对需要启动和促进 蜕膜化，因此是女性生育所必需的。在本建议中，我们将跟进我们的 令人兴奋的初步发现，并研究RA信号转导在蜕膜化过程中的作用， 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 在蜕膜化过程中需要RAR的组合，我们将阐明组织特异性 在围植入期RA信号的要求。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 RA和FGF信号，以及RA和同源结构域蛋白在蜕膜化过程中。成功 这个项目的完成将大大增加我们对RA信号的理解， 并将对植入生物学和药物治疗产生持久影响 的发现

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.