Hormone-Regulated Pathways Controlling Implantation and Fertility

描述(由申请人提供)：本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的激素途径。受精胚胎未能植入子宫内膜是不孕不育的主要原因。胚胎最初附着在子宫上皮后，会侵入子宫内膜间质，然后经历广泛的分化和重塑，即蜕膜化。着床和蜕膜化是一个复杂的过程，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。这项研究计划的中心假设是，这些激素信号通路的缺陷会导致子宫容受性不佳、蜕膜形成和早孕丢失。 基于DNA微阵列的基因表达谱和受体辅助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中的功能分析相结合，将为调节这一过程的荷尔蒙调节的分子网络提供蓝图。将这些分析扩展到从正常妇女和子宫内膜异位症(一种与生育力下降相关的常见妇科疾病)获得的子宫内膜组织，将提供这项研究的重要翻译组成部分。该计划由四个互补、协同的项目组成：(1)C/EBPβ在子宫蜕膜形成和植入中的作用，(2)核受体共同调节在着床和子宫功能中的作用，(3)通过BMP2途径调节基质分化和着床，以及(4)子宫内膜异位症作为蜕膜前功能障碍的临床模型。调查人员将得到一个监督项目间互动和数据共享的行政核心和一个提供细胞和组织中基因和蛋白质表达分析的显微镜核心的协助。 总而言之，我们的研究结果将提高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妇女不孕不育的原因。他们还应该帮助开发筛查子宫内膜功能障碍的新的分子诊断工具，并为不孕不育的治疗提供有针对性的治疗策略。

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.