PROJECT 4 - The Role of COUP - TFII in Endometrial Biology

项目 4 - COUP - TFII 在子宫内膜生物学中的作用

• 批准号: 7683513
• 负责人: Francesco John DeMayo
• 金额: $ 23.43万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683513
• 关键词: Ablation; Biological Assay; Biology; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Decidual Cell Reactions; Development; Disease; Endometrial; Endometrial Stromal Cell; Endometrium; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Erinaceidae; Estrogens; Female; Fertility; Functional disorder; Funding; Gene Expression; Gene Targeting; Genes; Genetically Engineered Mouse; Goals; Health; Hormones; Human; In Vitro; Infertility; Menstrual cycle; Modeling; Molecular; Mus; Nuclear Receptors; Ovarian Steroid Hormone; Pathway interactions; Pregnancy; Pregnancy Maintenance; Preparation; Process; Progesterone; Progesterone Receptors; RNA Interference; Regulation; Role; Signal Pathway; Signal Transduction; Simulate; Stromal Cells; Technology; Tissues; Uterine Diseases; Uterus; Vascularization; WNT4 gene; Xenograft Model; apoAI regulatory protein-1; biological research; cell stroma; chromatin immunoprecipitation; endometrial stroma; endometriosis; human tissue; in vitro Assay; knock-down; member; mouse model; natural Blastocyst Implantation; reproductive; small hairpin RNA; uterine receptivity

The overall objective of this proposal is to define the essential molecular mechanisms that underlie the role of COUP-TFII in the regulation of endometrial function in preparation of the uterus to support pregnancy and how alteration of these mechanisms results in endometrial dysfunction, such as endometriosis. During the last funding period, we have demonstrated, using genetically engineered mouse models, that COUP-TFII is critical in regulating the initiation of pregnancy by controlling the ability of the uterus to support embryo attachment, invasion, and the maintenance of pregnancy. COUP-TFII regulates these processes by controlling uterine epithelial cell sensitivity to estrogen, as well as, uterine stromal cell proliferation, vascularization, and differentiation by regulating Wnt and Epidermal Growth Factor (EGF) signaling pathways. Using primary human endometrial tissue, we have shown that this pathway is conserved in the human endometrium and COUP-TFII is critical for the ability of human endometrial stromal cells to differentiate in vitro. The goal of this proposal will be to investigate how COUP-TFII regulates endometrial epithelial ER signaling and stromal Wnt and EGFR signaling in the regulation of endometrial function and dysfunction. This will be accomplished by achieving the following aims: 1 .The importance of COUP-TFII regulation of endometrial epithelial E2 sensitivity in controlling uterine receptivity will be investigated. 2. The role of COUP-TFII in the regulation of human endometrial estrogen sensitivity will be determined. 3. The molecular mechanism by which COUP-TFII regulates the expression of target genes in human endometrial stromal cells will be investigated. 4. The role of EGFR in the ability of the PR-lhh-COUP-TFII axis to regulate endometrial function will be investigated. Accomplishment of these aims will define the molecular mechanisms regulating endometrial function and dysfunction.

该提案的总体目标是定义该作用的基本分子机制 COUP-TFII 在子宫内膜功能调节中的作用，为子宫支持妊娠做好准备 这些机制的改变如何导致子宫内膜功能障碍，例如子宫内膜异位症。期间 在上一个资助期间，我们使用基因工程小鼠模型证明了 COUP-TFII 通过控制子宫支持胚胎的能力来调节妊娠的开始至关重要 依恋、入侵和妊娠的维持。 COUP-TFII 通过以下方式调节这些过程 控制子宫上皮细胞对雌激素的敏感性以及子宫基质细胞增殖， 通过调节 Wnt 和表皮生长因子 (EGF) 信号传导实现血管化和分化 途径。使用原代人类子宫内膜组织，我们已经证明该途径在 人子宫内膜和 COUP-TFII 对于人子宫内膜基质细胞的能力至关重要 体外区分。该提案的目标是研究 COUP-TFII 如何调节子宫内膜 上皮 ER 信号传导以及基质 Wnt 和 EGFR 信号传导在子宫内膜功能调节中的作用 功能障碍。这将通过实现以下目标来实现： 1.COUP-TFII 的重要性 将研究子宫内膜上皮 E2 敏感性在控制子宫容受性中的调节。 2. 的 COUP-TFII 在调节人子宫内膜雌激素敏感性中的作用将被确定。 3. 的 COUP-TFII调控人子宫内膜靶基因表达的分子机制 将研究基质细胞。 4. EGFR在PR-lhh-COUP-TFII轴调节能力中的作用 将检查子宫内膜功能。这些目标的实现将定义分子 调节子宫内膜功能和功能障碍的机制。