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

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

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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.

项目摘要高级母校年龄（即≥35岁）被认为是先天缺陷的主要危险因素。在40岁以上的女性中年龄，赞助的赞助事件可能会增加到> 30％。非常关注卵巢功能和卵母细胞质量，但我们提供了子宫决策缺陷的证据可能是与年龄相关的生殖下降的主要原因。这个问题可能是由于孕酮钝（P4）引起的衰老子宫的反应性，通过其同源核受体PGR。 PGR是主调节器妊娠的建立和维持；但是，PGR的显着维度导致钝化激素反应作为子宫年龄。降低PGR表达的基本分子机制放松管制PGR靶基因可能解释了子宫衰老，这种机制仍然难以捉摸。我们的最近发现子宫sirtuin 1（SIRT1）是与年龄相关的PGR动作的关键驱动力基质细胞决定对我们对子宫生物学和生殖衰老的了解。通过删除子宫 SIRT1在小鼠中，我们生成了一种遗传模型（PGRCRE/+SIRT1F/F，即SIRT1D/D），用于对子宫的早熟研究由于PGR反应钝，与生理衰老相似。那将是首次尝试使用物理（46-54周龄）和遗传（缺乏SIRT1缺陷）老鼠模型的尝试发现哺乳动物生殖衰老的新子宫观点。该建议将提供第一个植入和决策的分子表征在过早的子宫衰老（遗传）的背景下老化; SIRT1D/d）通过多模式的单模式单细胞ATAC-SEQ/RNA-SEQ和比较分析生理衰老，鉴定常见基因特征，顺式调节元素和转录副因素建立和维持怀孕所需的子宫内膜细胞，但容易复制衰老。我们还将使用HTERT-RMORMATALIZED人子宫内膜将小鼠的发现转化为人类生物学基质细胞（T-HESC）作为基质细胞的决策是物理和遗传期间的主要缺陷老化。结合人与小鼠模型之间的多模式单细胞数据集以及功能通过CRISPR删除和激活来验证候选候选顺序调节元素和转录共同因素该建议分别将分别描述PGR动作所需的SIRT1响应性调节网络这种放松为子宫年龄。我们坚信我们的研究将为更深入，更全面在生殖衰老期间洞悉耐孕激素子宫内膜。有了新知识，研究可以采取策略来抵消衰老对妊娠结局的不利影响。