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：
Xiaoqiu Wang
金额：
$ 56.04万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
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：
https://reporter.nih.gov/project-details/10636576
关键词：
ATAC-seq Ablation Abnormal placentation Acceleration Address Adverse effects Age Age Years Aging Aneuploidy Attention Binding Biological Assay Biological Process Biology Biology of Aging CRISPR-mediated transcriptional activation CRISPR/Cas technology Cell Proliferation Cell Survival Cells ChIP-seq Clustered Regularly Interspaced Short Palindromic Repeats Collagen Communication Congenital Abnormality Data Set Deacetylase Decidual Cell Reactions Defect Deposition Endometrial Endometrial Stromal Cell Endometrium Environment Epithelium Estrogens Female Fertility Fetal Growth Retardation Genes Genetic Genetic Models Genetic Transcription Goals Hormonal Hormone Responsive Human Human Biology In Vitro Incidence Infertility Inflammation Invaded Knowledge Litter Size Mediating Modeling Molecular Mus Nature Nuclear Receptors Ovarian Physiological Physiology Placentation Population Predisposition Pregnancy Pregnancy Maintenance Pregnancy Outcome Premature Birth Progesterone Proliferating Regulation Regulatory Element Reproduction Reproductive Health Research Resistance Resolution Risk Risk Factors Role SIRT1 gene Signal Transduction Small Interfering RNA Spontaneous abortion Sterility Stromal Cells System Translating Uterus Wild Type Mouse Woman Women&apos s Health Work advanced maternal age adverse pregnancy outcome age effect age related aged blastocyst candidate validation cofactor comparative conditional mutant congenital heart disorder fetal gene regulatory network genetic signature human model implantation in vivo insight knock-down migration mouse model multimodality mutant mouse model natural Blastocyst Implantation new therapeutic target novel oocyte quality premature reproductive reproductive senescence response senescence single-cell RNA sequencing transcription regulatory network transcriptome sequencing uterine 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.

项目概要高龄产妇（即≥35岁）被认为是40岁以上女性出生缺陷的主要危险因素。随着年龄的增长，自然流产的发生率可增加至>30%，已引起人们的广泛关注。卵巢功能和卵母细胞质量，但我们提供的证据表明子宫蜕膜化缺陷可能是一个与年龄相关的生殖能力下降的主要原因可能是黄体酮 (P4) 减弱所致。老化子宫的反应性，通过其同源核受体 PGR 来调节。然而，PGR 的显着降低会导致妊娠的建立和维持；随着子宫年龄的增长，激素反应减少 PGR 表达的潜在分子机制。放松 PGR 靶基因可能是子宫衰老的原因，而这一机制至今仍难以捉摸。最近发现子宫 Sirtuin 1 (SIRT1) 是年龄相关 PGR 作用的关键驱动因素，通过该作用，子宫内膜基质细胞蜕膜通过消除子宫影响我们对子宫生物学和生殖衰老的了解。 SIRT1在小鼠中，我们生成了遗传模型（PgrCre/+Sirt1f/f，即Sirt1d/d）用于子宫早衰的研究由于与生理衰老相关的 PGR 反应迟钝，因此，本研究将是这样的。首次尝试使用生理（46-54周龄）和遗传（Sirt1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提供第一个。子宫早衰背景下植入和蜕膜化的分子特征（遗传老化；Sirt1d/d) 通过一体化多模式单细胞 ATAC-seq/RNA-seq 以及与生理衰老，识别常见基因特征、顺式调控元件和转录辅助因子子宫内膜细胞是建立和维持妊娠所需的，但易受生殖衰老的影响。我们还将使用 hTERT 永生化人类子宫内膜将小鼠的研究结果转化为人类生物学基质细胞（T-HESCs）作为基质细胞的蜕膜化是生理和遗传过程中的主要缺陷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。通过 CRISPR 删除和激活验证候选顺式调控元件和转录辅助因子该提案将分别描述 PGR 行动所需的 SIRT1 响应监管网络我们坚信，我们的研究将提供更深入、更全面的信息。借助这些新知识和研究，深入了解生殖衰老过程中的孕酮抵抗子宫内膜。可以采取策略来抵消衰老对妊娠结局的不利影响。