Molecular Analysis of Uterine Receptivity

子宫容受性的分子分析

• 批准号: 7602927
• 负责人: Francesco John DeMayo
• 金额: $ 30.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602927
• 关键词: Ablation; Affect; Cell Proliferation; Cells; Communication; Complex; DNA; Data; Decidual Reaction; Defect; Disease; Endometrial; Endometrial Carcinoma; Epithelial; Epithelium; Erinaceidae; Estrogen Receptor alpha; Estrogens; Failure; Fetal Development; Funding; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; In Vitro; Infertility; Molecular; Molecular Analysis; Mus; Nuclear Receptors; Ovarian Steroid Hormone; Pathway interactions; Phenotype; Physiological; Pregnancy; Preparation; Progesterone; Progesterone Receptors; Regulation; Role; Signal Pathway; Signal Transduction; Steroids; Technology; Testing; Uterus; Vascularization; Women' s Health; endometrial stroma; endometriosis; implantation; in vivo; leukemia inhibitory factor; member; morphogens; natural Blastocyst Implantation; novel; paracrine; preimplantation; public health relevance; receptor; uterine receptivity

DESCRIPTION (provided by applicant): The overall objective of this proposal is to define the essential molecular mechanisms that underlie the preparation of the uterus to support embryo implantation. Specifically, this proposal will investigate the molecular pathways regulated by the ovarian steroid hormone, progesterone (P4), in the pre-implantation uterus. P4 acting through its cognate nuclear receptor, the progesterone receptor (PR), regulates the transcription of genes which coordinate the ability of the uterus to support embryo implantation and fetal development. Alterations in P4 signaling are associated with endometrial diseases, such as infertility, endometriosis and endometrial cancer. During the last funding period, we have demonstrated that conditional ablation of Ihh in the murine uterus results in loss of stroma cell proliferation, vascularization, and differentiation. This phenotype resulted in the inability of the uterus to undergo the post-implantation decidual reaction. In addition to the regulation of endometrial stroma function, inactivation of Ihh signaling interfered with the ability of the endometrial epithelium to support embryo attachment and invasion. We have preliminary data illustrating that ablation of Ihh results in an increase in the expression of Estrogen Receptor alpha (ER1) and estrogen (E2) regulated genes in the endometrial epithelium. The first goal of this application is to test the hypothesis that the increased E2 sensitivity in the uterine epithelium is the cause of the implantation defect due to loss of Ihh expression. We will then further investigate the interaction of the P4 regulated Ihh pathway with E2 signaling by determining the regulation by and role of Ihh in the Leukemia Inhibitory Factor (Lif) signaling axis, an E2 regulated pathway that is critical for normal implantation. Finally, given the importance of the PR-Ihh axis in the regulation of uterine function, we will define the molecular mechanism by which PR regulates the expression of Ihh. This will be accomplished in three specific aims. (1) The physiological significance of the increased E2 signaling in the endometrial epithelium after ablation of Ihh on uterine receptivity will be investigated. (2) The interaction of the Ihh signaling axis with that of the E2 regulated Leukemia Inhibitory Factor (Lif) signaling axis in the preparation the uterus for embryo implantation will be identified. (3) The molecular mechanism by which endometrial epithelial PR regulates the expression of Ihh and uterine function will be defined in vivo. The completion of the aims of this proposal will define the role of P4 regulated pathways in the regulation of uterine epithelial function. PUBLIC HEALTH RELEVANCE: Infertility, endometriosis, and endometrial cancer have a large affect on women's health. This project will determine the role the steroid, progesterone has on these diseases.

描述（由申请人提供）：该提案的总体目标是定义基于子宫制备以支持胚胎植入的基本分子机制。具体而言，该建议将研究由植入前子宫中卵巢类固醇激素（P4）调节的分子途径。 P4通过其同源核受体（PR）作用，调节基因的转录，这些基因协调子宫支持胚胎植入和胎儿发育的能力。 P4信号传导的改变与子宫内膜疾病有关，例如不育，子宫内膜异位症和子宫内膜癌。在最后一个资金期间，我们证明了鼠子宫中IHH的条件消融导致基质细胞增殖，血管化和分化的丧失。这种表型导致子宫无法进行植入后的判断反应。除了调节子宫内膜基质功能外，IHH信号传导的灭活还干扰了子宫内膜上皮支持胚胎附着和侵袭的能力。我们有初步数据表明，IHH的消融导致子宫内膜上皮细胞中雌激素受体α（ER1）和雌激素（E2）调控基因的表达增加。该应用的第一个目标是检验以下假设：子宫上皮中E2敏感性的提高是由于IHH表达丧失而导致植入缺陷的原因。然后，我们将通过确定IHH在白血病抑制因子（LIF）信号轴上的调控，进一步研究P4调节的IHH途径与E2信号传导的相互作用，这是一种对正常植入至关重要的E2调节途径。最后，鉴于PR-IHH轴对子宫功能的调节的重要性，我们将定义PR调节IHH表达的分子机制。这将以三个具体目标来实现。 （1）将研究IHH在子宫接受能力上的子宫内膜上皮中E2信号增加的生理意义。 （2）IHH信号轴与E2调节的白血病抑制因子（LIF）信号传导轴的相互作用将被鉴定为胚胎植入子宫。 （3）子宫内膜上皮PR调节IHH和子宫功能的表达的分子机制将在体内定义。该提案目标的完成将定义P4调节途径在子宫上皮功能调节中的作用。公共卫生相关性：不育，子宫内膜异位症和子宫内膜癌对妇女健康有很大影响。该项目将确定类固醇对这些疾病的作用。