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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：
10217213
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/10217213
关键词：
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 Embryo Embryonic Development Endometrial Endometrial Stromal Cell Endometrium Engineering Epithelial Epithelial Cells Event Female infertility Fertility Future Gene Expression Profile Genetic Transcription Genomics Goals Growth High Risk Woman Human Impairment In Vitro Individual Infertility Knowledge Mediating Mediator of activation protein 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 base 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.

项目摘要胚胎植入失败是全世界妇女不孕症的一个重要原因。在我们对卵母细胞和胚胎发育的理解中，部分由于子宫内膜不接受胚胎而保持不可接受的低水平。为成功着床、子宫内膜容受性和随后的蜕膜化需要协调的孕酮（P4）以细胞类型特异性方式进行信号传导。虽然支持P4-β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作用的关键介质的知识，在这些这种知识的缺乏是重要的，因为没有什么短的识别关键的早期支持P4-β受体驱动的子宫容受性的信号将解决目前诊断和治疗子宫内膜异位症的临床局限性。在分子水平上治疗非受体子宫。为了解决这个问题，我们最近证明了早幼粒细胞白血病锌指（PLZF）转录因子是孕酮的直接靶点，受体（PGR），是培养的人子宫内膜间质P4-β依赖性蜕膜化所必需的作为PLZF在人子宫内膜中P4介导作用的进一步翻译支持，人子宫内膜活检组织中PLZF表达水平在P4-β显性周期中显著诱导在妊娠早期的小鼠中，Plzf被诱导，在接受子宫的上皮和间质区室中，在蜕膜细胞中强烈表达，这些发现支持了我们的假设，PLZF（及其下游转录因子程序）作为P4-β依赖性子宫容受性和蜕膜化的关键介质，子宫内膜细胞类型特异性的方式。这一假设将通过三个特定的目的进行检验。使用最近的产生的携带Plzf条件等位基因的小鼠模型，特异性目的1将建立体内重要性 Plzf（及其转录程序）在P4-β依赖的子宫内膜容受性和蜕膜化中的作用。在小鼠子宫内膜中的上皮和间质Plzf信号传导的个体贡献的剖析围着床期将是具体目标2的主要焦点。我们最近证明， PLZF对早期生长反应1（EGR 1）转录因子的转录抑制是 hESC蜕膜化;阻断这种调节会损害hESC的蜕膜化。然而，在蜕膜化之前，蜕膜前hESC中的EGR 1是这些细胞蜕膜化所必需的，这表明EGR 1“启动”了蜕膜前hESC。具体目标3将通过对蜕膜hESC进行分子表征来解决这一问题。 P4-β PGR-β PLZF-β EGR 1调节轴是体外和体内蜕膜化所必需的。这些目标将使用最先进的基因工程小鼠研究Plzf在子宫内膜容受性和蜕膜化中的作用，以及高通量的基因组规模的方法来鉴定新的子宫内膜靶点， Plzf和转录相互作用体，通过这种调节发生。