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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.

项目总结/文摘