Deciphering molecular mechanisms controlling age-associated uterine adaptabilityto pregnancy
破译控制与年龄相关的子宫妊娠适应性的分子机制
基本信息
- 批准号:10636576
- 负责人:
- 金额:$ 56.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAblationAbnormal placentationAccelerationAddressAdverse effectsAgeAge YearsAgingAneuploidyAttentionBindingBiological AssayBiological ProcessBiologyBiology of AgingCRISPR-mediated transcriptional activationCRISPR/Cas technologyCell ProliferationCell SurvivalCellsChIP-seqClustered Regularly Interspaced Short Palindromic RepeatsCollagenCommunicationCongenital AbnormalityData SetDeacetylaseDecidual Cell ReactionsDefectDepositionEndometrialEndometrial Stromal CellEndometriumEnvironmentEpitheliumEstrogensFemaleFertilityFetal Growth RetardationGenesGeneticGenetic ModelsGenetic TranscriptionGoalsHormonalHormone ResponsiveHumanHuman BiologyIn VitroIncidenceInfertilityInflammationInvadedKnowledgeLitter SizeMediatingModelingMolecularMusNatureNuclear ReceptorsOvarianPhysiologicalPhysiologyPlacentationPopulationPredispositionPregnancyPregnancy MaintenancePregnancy OutcomePremature BirthProgesteroneProliferatingRegulationRegulatory ElementReproductionReproductive HealthResearchResistanceResolutionRiskRisk FactorsRoleSIRT1 geneSignal TransductionSmall Interfering RNASpontaneous abortionSterilityStromal CellsSystemTranslatingUterusWild Type MouseWomanWomen&aposs HealthWorkadvanced maternal ageadverse pregnancy outcomeage effectage relatedagedblastocystcandidate validationcofactorcomparativeconditional mutantcongenital heart disorderfetalgene regulatory networkgenetic signaturehuman modelimplantationin vivoinsightknock-downmigrationmouse modelmultimodalitymutant mouse modelnatural Blastocyst Implantationnew therapeutic targetnoveloocyte qualityprematurereproductivereproductive senescenceresponsesenescencesingle-cell RNA sequencingtranscription regulatory networktranscriptome sequencinguterine receptivity
项目摘要
PROJECT SUMMARY
Advanced maternal age (i.e., ≥35 years old) is considered a major risk factor for birth defects. In women over 40
years of age, the incidence of spontaneous abortion can increase to >30%. Much attention has been focused on
ovarian function and oocyte quality, but we provide evidence that uterine decidualization defects could be a
major cause of age-related reproductive decline. This problem is likely due to a blunted progesterone (P4)
responsiveness of the aging uterus, via its cognate nuclear receptor PGR. PGR is the master regulator for the
establishment and maintenance of pregnancy; however, a significant diminution in PGR results in a blunted
hormonal response as the uterus ages. The underlying molecular mechanisms that diminish expression of PGR
and deregulate PGR target genes likely account for uterine aging, a mechanism that has remained elusive. Our
recent discovery of uterine Sirtuin 1 (SIRT1) as a critical driver of age-related PGR action by which endometrial
stromal cells decidualize impacts our knowledge of uterine biology and reproductive aging. By deleting uterine
SIRT1 in mice, we generated a genetic model (PgrCre/+Sirt1f/f, i.e. Sirt1d/d) for research on premature uterine aging
due to blunted PGR response that are similar to those associated with physiologic aging. Thus, this study will be
the first attempt to use physiological (46-54 weeks of age) and genetic (Sirt1-deficient) aging mouse models
to discover a novel uterine perspective of mammalian reproductive aging. This proposal will provide the first
molecular characterization of implantation and decidualization in the context of premature uterine aging (genetic
aging; Sirt1d/d) by all-in-one multimodal single-cell ATAC-seq/RNA-seq and comparative analyses with
physiologic aging, identifying common gene signatures, cis-regulatory elements and transcriptional co-factors in
endometrial cells required for establishment and maintenance of pregnancy but susceptible to reproductive aging.
We will also translate the findings in mice to human biology using hTERT-immortalized human endometrial
stromal cells (T-HESCs) as decidualization of stromal cells are major defects during physiological and genetic
aging. Combined with multimodal single cell datasets between human and mouse models, as well as functional
validation of candidate cis-regulatory elements and transcriptional co-factors by CRISPR deletion and activation
systems, respectively, this proposal will delineate SIRT1-responsive regulatory network required for PGR actions
that deregulate as uterus ages. We strongly believe that our study will give a deeper and more comprehensive
insight into progesterone-resistant endometrium during reproductive aging. With that new knowledge, research
can pursue strategies to counteract adverse effects of aging on outcomes of pregnancy.
项目摘要
高龄产妇(即,≥35岁)被认为是出生缺陷的主要危险因素。在40岁以上的女性中
岁时,自然流产的发生率可增加到> 30%。许多注意力都集中在
卵巢功能和卵母细胞的质量,但我们提供的证据表明,子宫蜕膜化缺陷可能是一个
年龄相关性生殖衰退的主要原因。这个问题可能是由于钝孕激素(P4)
衰老子宫的反应性,通过其同源核受体PGR。PGR是
妊娠的建立和维持;然而,PGR的显著降低导致
随着子宫年龄的增长,荷尔蒙的反应。减少PGR表达的潜在分子机制
和PGR靶基因的失调可能是子宫衰老的原因,这是一种仍然难以捉摸的机制。我们
最近发现子宫Sirtuin 1(SIRT 1)是年龄相关性PGR作用的关键驱动因素,
基质细胞蜕膜化影响我们对子宫生物学和生殖衰老的认识。删除子宫
Sirt 1基因在小鼠体内的表达,我们建立了一个用于研究子宫早衰的遗传模型(PgrCre/+ Sirt 1f/f,即Sirt 1d/d
由于PGR反应减弱,与生理衰老相关的反应相似。因此,本研究将
首次尝试使用生理(46-54周龄)和遗传(Sirt 1缺陷)衰老小鼠模型
发现哺乳动物生殖衰老的新子宫视角。该提案将首次提供
在子宫过早老化的背景下着床和蜕膜化的分子特征(遗传学)
老化; Sirt 1d/d)通过多合一多模式单细胞ATAC-seq/RNA-seq和与
生理老化,确定共同的基因签名,顺式调控元件和转录辅因子,
子宫内膜细胞是建立和维持妊娠所必需的,但易受生殖衰老的影响。
我们还将使用hTERT永生化的人子宫内膜将小鼠中的发现转化为人类生物学
间质细胞(T-HESC)作为间质细胞的蜕膜化是生理和遗传过程中的主要缺陷,
衰老结合人类和小鼠模型之间的多模式单细胞数据集,以及功能性
通过CRISPR缺失和激活验证候选顺式调控元件和转录辅因子
本提案将描述PGR行动所需的SIRT 1响应监管网络
随着子宫年龄的增长而失调。我们坚信,我们的研究将为我们提供一个更深入、更全面的
深入了解生殖衰老过程中对孕酮耐药的子宫内膜。有了这些新知识,研究
可以采取策略来抵消衰老对怀孕结果的不利影响。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Xiaoqiu Wang其他文献
Xiaoqiu Wang的其他文献
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{{ truncateString('Xiaoqiu Wang', 18)}}的其他基金
TET2 as a novel epigenetic regulator for uterine function and fertility
TET2 作为子宫功能和生育力的新型表观遗传调节因子
- 批准号:
10725828 - 财政年份:2023
- 资助金额:
$ 56.04万 - 项目类别:
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