Hormone-Regulated Pathways Controlling Implantation and Fertility

控制着床和生育能力的激素调节途径

• 批准号: 8053371
• 负责人: MILAN K BAGCHI
• 金额: $ 131.8万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-07 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053371
• 关键词: Hormone; Regulated; Pathways; Controlling; Implantation

DESCRIPTION (provided by applicant): The overall objective of this U54 application is to characterize, at molecular and cellular levels, the hormonal pathways that regulate embryo implantation and fertility. Failure of the fertilized embryo to implant into the endometrium is a major cause of infertility. Following its initial attachment to the uterine epithelium, the embryo invades the endometrial stroma, which then undergoes extensive differentiation and remodeling, known as decidualization. Implantation and decidualization are complex processes driven by a cascade of signaling events regulated by the steroid hormones estrogen and progesterone. The central hypothesis of this research program is that defects in these hormonal signaling pathways lead to improper uterine receptivity, decidualization and early pregnancy loss. DNA microarray-based gene expression profiling and receptor-coregulator analyses have revealed novel steroid-regulated pathways, providing important insights into the cellular mechanisms by which implantation is controlled. Combination of this new knowledge with functional analysis in gene knockout mouse models will provide a blueprint of the molecular networks that mediate the hormonal regulation of this process. Extension of these analyses to endometrial tissues obtained from normal women as well as those with endometriosis, a common gynecologic disorder associated with reduced fertility, will provide the important translational component of this research. The program is comprised of four complementary, synergistic projects: (1) Role of C/EBP beta in Uterine Decidualization and Implantation, (2) Nuclear Receptor Co-regulators in Implantation and Uterine Function, (3) Regulation of Stromal Differentiation and Implantation by the BMP2 Pathway, and (4) Endometriosis as a Clinical Model of Predecidual Dysfunction. Investigators will be aided by an Administrative Core that will oversee inter-project interactions and data sharing, and a Microscopy Core that will provide gene and protein expression analyses in cells and tissues. In summary, the results of our studies should improve understanding of the mechanisms and cellular pathways that control implantation and help identify factors that underlie infertility in women with endometriosis. They should also aid in developing new molecular diagnostic tools for screening endometrial dysfunction and enable targeted therapeutic strategies for the treatment of infertility.

描述（由申请人提供）：该 U54 申请的总体目标是在分子和细胞水平上表征调节胚胎植入和生育力的激素途径。受精胚胎未能植入子宫内膜是导致不孕的主要原因。在最初附着于子宫上皮后，胚胎侵入子宫内膜基质，然后经历广泛的分化和重塑，称为蜕膜化。着床和蜕膜化是由类固醇激素雌激素和黄体酮调节的一系列信号事件驱动的复杂过程。该研究项目的中心假设是，这些激素信号通路的缺陷会导致子宫容受性不当、蜕膜化和早期妊娠流产。 基于 DNA 微阵列的基因表达谱和受体共调节因子分析揭示了新的类固醇调节途径，为控制植入的细胞机制提供了重要的见解。将这一新知识与基因敲除小鼠模型的功能分析相结合，将提供介导这一过程的激素调节的分子网络的蓝图。将这些分析扩展到从正常女性以及患有子宫内膜异位症（一种与生育能力下降相关的常见妇科疾病）的子宫内膜组织，将为这项研究提供重要的转化部分。该计划由四个互补、协同的项目组成：(1) C/EBP beta 在子宫蜕膜化和着床中的作用，(2) 核受体协同调节剂在着床和子宫功能中的作用，(3) 基质分化和着床的调节BMP2 通路，以及 (4) 子宫内膜异位症作为蜕膜前功能障碍的临床模型。 研究人员将得到管理核心的帮助，该核心将监督项目间的交互和数据共享，以及显微镜核心将提供细胞和组织中的基因和蛋白质表达分析。 总之，我们的研究结果应该增进对控制着床的机制和细胞途径的理解，并有助于确定子宫内膜异位症女性不孕的潜在因素。他们还应该帮助开发新的分子诊断工具来筛查子宫内膜功能障碍，并为治疗不孕症制定针对性的治疗策略。