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:
- 金额:$ 33.86万
- 依托单位:
- 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:
- 关键词:Abnormal placentationBiologyBirthCell CommunicationCell modelCellsConceptusContraceptive AgentsDataDecidual CellDecidual Cell ReactionsDefectDevelopmentDominant-Negative MutationEndometrial Stromal CellEpithelialExhibitsFailureFertilization in VitroFetal GrowthFibroblast Growth FactorFibroblastsGene Expression ProfilingGene ProteinsGene SilencingGenesGeneticGenetic TranscriptionGrowth FactorHomeodomain ProteinsHumanImplantInfertilityKnock-outKnockout MiceLeadLimb DevelopmentLoxP-flanked alleleMediatingMusMutant Strains MicePathway interactionsPhenotypePregnancyProceduresProcessProgesteroneProlactinRegulator GenesReportingReproductionRetinoic Acid ReceptorScreening procedureSignal PathwaySignal TransductionSmall Interfering RNASystemTechnologyTissuesTretinoinUterusadverse pregnancy outcomebaseconditional knockoutdrug discoveryendometriosisfailure Implantationfemale fertilityfollow-upgene synthesisgenome-widehigh throughput screeninghormonal signalshuman embryonic stem cellimplantationimprovedloss of functionmouse modelnatural Blastocyst Implantationnovelpregnancy failurepromoterresponsescreeningsuccesstooltranscriptome sequencingwhole 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
项目成果
期刊论文数量(0)
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膀胱癌中的雄激素和 Wnt 信号传导
- 批准号:
10727745 - 财政年份:2023
- 资助金额:
$ 33.86万 - 项目类别:
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$ 33.86万 - 项目类别:
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