Retinoic acid signaling in decidualization

蜕膜化中的视黄酸信号传导

• 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
• 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

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.

项目摘要/摘要 人不育是一个全球问题，胚胎植入的失败是重要的 自然怀孕和体外受精程序期间的妊娠衰竭百分比。 植入是一个非常复杂的过程，需要精确控制的激素信号传导， 生长因子信号传导和细胞 - 细胞相互作用。 deDialization是植入中必需的步骤 过程。它涉及成纤维细胞样子宫基质细胞的快速增殖和分化 进入上皮样细胞。这些细胞成为围绕该组织的一部分 植入概念。义词化缺陷可以直接导致植入失败。而且，很早 斜视缺陷会导致其他不良妊娠结局，包括异常胎盘， 宫内胎儿的生长和早期分娩受限。理解义词化对 提高IVF成功率，开发新颖的避孕药并发现新的治疗方法 子宫内膜异位症。尽管它在繁殖方面具有重要意义 直到我们最近开发合适的高吞吐量筛选，从未系统地研究 工具，永生化的人子宫内膜基质细胞，在下面携带黄色荧光蛋白基因 孕激素敏感性催乳素启动子（PRL-Y细胞）的控制。我们最近使用了prl-y 细胞执行整个基因组siRNA功能筛选，以发现人类的新调节基因 十字无限。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deDIDAILIAD的教条相反，我们提出了一个 范式转移假设，即启动和促进RA信号绝对需要RA信号传导 义词化，因此是女性生育需要的。在此提案中，我们将跟进我们的 令人兴奋 仔细映射其下游信号通路。在目的中，我将确定哪个rar或 在划分期间需要稀有的组合，我们将阐明组织特异性 植入周期期间RA信号的要求。在AIM II中，我们将确定RA下游目标 在小鼠和人类中的分解过程中。最后，在AIM III中，我们将研究 RA和FGF信号传导，在deidualized期间RA和同源域蛋白之间。成功的 该项目的完成将大大增加我们对RA信号传导的理解 植入/deDialation，将对植入生物学和药物产生持久的影响 发现。