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Molecular Analysis of Uterine Receptivity

子宫容受性的分子分析

基本信息

批准号：
10663198
负责人：
JOHN P LYDON
金额：
$ 33.32万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663198
关键词：
Ablation Address Advanced Development Alleles Assisted Reproductive Technology Biopsy CRISPR/Cas technology Cell Compartmentation Cell physiology Cells Clinical Cre driver Decidua Decidual Cell Decidual Cell Reactions Development Diagnosis Diagnostic Early identification Embryo Embryonic Development Endometrial Endometrial Stromal Cell Endometrium Engineering Epithelial Cells Epithelium Event Female infertility Fertility Future Gene Expression Profile Genes Genetic Transcription Genomics Goals Growth High Risk Woman Human Impairment In Vitro Individual Infertility Knowledge Mediating Mediator Menstrual cycle Molecular Molecular Analysis Mus National Institute of Child Health and Human Development Oocytes Outcome Study Phase Pregnancy Pregnancy loss Process Progesterone Progesterone Receptors Regulation Regulatory Element Reporting Reproductive Health Role Signal Transduction Spontaneous abortion Stromal Cells Testing Therapeutic Transcriptional Regulation Uterus Woman ZNF145 gene cell type clinically relevant clinically significant early pregnancy failure Implantation gene repression genome-wide implantation improved improved outcome in vivo insight mouse model natural Blastocyst Implantation novel pre-clinical pregnancy failure pregnant prognostic programs promoter reproductive outcome response success transcription factor transcriptome uterine receptivity

项目摘要

Project Summary Embryo implantation failure is a significant causal factor of infertility for women worldwide. Although advances in our understanding of oocyte and embryo development have improved pregnancy success rates, these rates remain unacceptably low due in part to an endometrium that is nonreceptive to the embryo. For successful implantation, endometrial receptivity and subsequent decidualization requires coordinated progesterone (P4) signaling in a cell-type specific manner. While the signature cellular events that underpin P4-driven uterine receptivity and decidualization are known, our knowledge of the pivotal mediators of P4 action in these processes is incomplete. This knowledge-deficiency is significant as nothing short of identifying the key early signals that underpin P4-driven uterine receptivity will address the current clinical limitations in diagnosing and treating a non-receptive uterus at the molecular level. To address this deficiency, we recently demonstrated that the promyelocytic leukemia zinc finger (PLZF) transcription factor is a direct target of the progesterone receptor (PGR) and is indispensable for P4-dependent decidualization of cultured human endometrial stromal cells (hESCs). As further translational support for a P4 mediator role for PLZF in the human endometrium, PLZF expression levels in human endometrial biopsies are significantly induced during the P4-dominant secretory phase of the human non-conception menstrual cycle. In the early pregnant mouse, Plzf is induced in the epithelial and stromal compartments of the receptive uterus and is strongly expressed in decidual cells with pregnancy progression. These findings support our hypothesis that PLZF (and its downstream transcriptional program) acts as a pivotal mediator of P4-dependent uterine receptivity and decidualization and does so in an endometrial cell-type specific manner. This hypothesis will be tested by three specific aims. Using a recently generated mouse model carrying a Plzf conditional allele, Specific Aim 1 will establish the in vivo importance of Plzf (and its transcriptional programs) in P4-dependent endometrial receptivity and decidualization. Dissecting the individual contributions of epithelial and stromal Plzf signaling in the murine endometrium during the periimplantation period will be a major focus of Specific Aim 2. We recently demonstrated that direct transcriptional repression of the early growth response 1 (EGR1) transcription factor by PLZF is required for hESC decidualization;; blocking this regulation impairs hESC decidualization. Prior to decidualization, however, EGR1 in pre-decidual hESCs is required for these cells to decidualize, suggesting that EGR1 “primes” the pre- decidual hESC for decidualization. Specific Aim 3 will address this proposal by molecularly characterizing the P4-PGR-PLZF-EGR1 regulatory axis that is required for in vitro and in vivo decidualization. These aims will use state-of-the-art engineered mice to study the role of Plzf in endometrial receptivity and decidualization as well as high throughput genome-scale approaches to identify novel endometrial targets directly regulated by Plzf and the transcriptional interactome through which this regulation occurs.

项目摘要胚胎着床失败是全世界女性不孕的一个重要原因。虽然取得了进展根据我们对卵母细胞和胚胎发育的了解，提高了怀孕成功率，这些比率保持在不可接受的低水平，部分原因是子宫内膜不接受胚胎。为了成功着床、子宫内膜容受性和随后的蜕膜化需要协调黄体酮 (P4) 以细胞类型特异性方式发出信号。虽然支持 P4 驱动子宫的标志性细胞事件接受性和蜕膜化是已知的，我们对 P4 作用的关键介体的了解流程不完整。这种知识的缺乏是很重要的，因为无非就是及早识别关键支持 P4 驱动的子宫容受性的信号将解决当前诊断和治疗方面的临床局限性在分子水平上治疗非容受性子宫。为了解决这个缺陷，我们最近证明了早幼粒细胞白血病锌指 (PLZF) 转录因子是黄体酮的直接靶标受体 (PGR)，对于培养的人类子宫内膜基质的 P4 依赖性蜕膜化是不可或缺的细胞（hESC）。作为对 PLZF 在人类子宫内膜中 P4 介导作用的进一步转化支持，人类子宫内膜活检中 PLZF 的表达水平在 P4 主导的过程中显着诱导人类非受孕月经周期的分泌期。在怀孕早期的小鼠中，Plzf 被诱导接受子宫的上皮和间质室，并在蜕膜细胞中强烈表达怀孕进展。这些发现支持我们的假设，即 PLZF（及其下游转录程序）作为 P4 依赖性子宫容受性和蜕膜化的关键调节剂，并且在子宫内膜细胞类型特定的方式。这一假设将通过三个具体目标进行检验。最近使用生成的携带 Plzf 条件等位基因的小鼠模型，具体目标 1 将确定体内重要性 Plzf（及其转录程序）在 P4 依赖性子宫内膜容受性和蜕膜化中的作用。剖析小鼠子宫内膜中上皮和间质 Plzf 信号传导的个体贡献植入期间将是具体目标 2 的主要焦点。我们最近证明，直接 PLZF 对早期生长反应 1 (EGR1) 转录因子的转录抑制是 hESC 蜕膜化；；阻断此调节会损害 hESC 蜕膜化。然而，在蜕膜化之前，蜕膜前的 hESC 中的 EGR1 是这些细胞蜕膜化所必需的，这表明 EGR1“启动”了蜕膜前的 hESC 用于蜕膜化的蜕膜 hESC。具体目标 3 将通过分子表征来解决该提案 P4-PGR-PLZF-EGR1 调节轴是体外和体内蜕膜化所需的。这些目标将使用最先进的基因工程小鼠来研究 Plzf 在子宫内膜容受性和蜕膜化中的作用，如下所示以及高通量基因组规模方法来识别直接调控的新子宫内膜靶点 Plzf 和转录相互作用组，通过它发生这种调节。

项目成果

期刊论文数量（65）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Perturbing the cellular levels of steroid receptor coactivator-2 impairs murine endometrial function.

DOI：
10.1371/journal.pone.0098664
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Szwarc MM;Kommagani R;Jeong JW;Wu SP;Tsai SY;Tsai MJ;O'Malley BW;DeMayo FJ;Lydon JP
通讯作者：
Lydon JP

Cell-type specific analysis of physiological action of estrogen in mouse oviducts.

DOI：
10.1096/fj.202002747r
发表时间：
2021-05
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
McGlade EA;Herrera GG;Stephens KK;Olsen SLW;Winuthayanon S;Guner J;Hewitt SC;Korach KS;DeMayo FJ;Lydon JP;Monsivais D;Winuthayanon W
通讯作者：
Winuthayanon W

Decidualization of human endometrial stromal cells requires steroid receptor coactivator-3.

DOI：
10.3389/frph.2022.1033581
发表时间：
2022
期刊：
FRONTIERS IN REPRODUCTIVE HEALTH
影响因子：
0
作者：
Maurya, Vineet K;Szwarc, Maria M;Lonard, David M;Gibbons, William E;Wu, San-Pin;O'Malley, Bert W;DeMayo, Francesco J;Lydon, John P
通讯作者：
Lydon, John P

Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice.

DOI：
10.1038/srep20242
发表时间：
2016-02-02
期刊：
Scientific reports
影响因子：
4.6
作者：
Kim YS;Kim HR;Kim H;Yang SC;Park M;Yoon JA;Lim HJ;Hong SH;DeMayo FJ;Lydon JP;Choi Y;Lee DR;Song H
通讯作者：
Song H

The NR2F2-HAND2 signaling axis regulates progesterone actions in the uterus at early pregnancy.