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: 7932567
• 负责人: MILAN K BAGCHI
• 金额: $ 28.26万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932567
• 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应用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能力的激素途径。受精的胚胎植入子宫内膜的失败是不孕的主要原因。在其最初依赖子宫上皮后，胚胎会侵入子宫内膜基质，然后经历了广泛的分化和重塑，称为deciDualization。植入和斜视是由类固醇激素雌激素和孕酮调节的一系列信号事件驱动的复杂过程。该研究计划的中心假设是这些激素信号通路中的缺陷导致子宫接受能力不当，决定和早期妊娠丧失。 基于DNA微阵列的基因表达分析和受体调节剂分析已经揭示了新型类固醇调节的途径，从而提供了对控制植入的细胞机制的重要见解。在基因敲除小鼠模型中，这种新知识与功能分析的结合将提供介导该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妇女获得的子宫内膜组织以及子宫内膜异位症的子宫内膜组织，这是一种与生育率降低相关的常见妇科疾病，将为这项研究提供重要的翻译成分。该计划由四个互补的协同项目组成：（1）C/EBPβ在子宫de骨化和植入中的作用，（2）核受体共同调节剂在植入和子宫功能中的作用，（3）通过植入和子宫功能调节静脉分化和植入的核受体共同调节器BMP2途径和（4）子宫内膜异位症是前性功能障碍的临床模型。 研究人员将得到一个管理核心的帮助，该核心将监督项目间相互作用和数据共享，以及将在细胞和组织中提供基因和蛋白质表达分析的显微镜核心。 总而言之，我们的研究结果应提高对控制植入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因素。他们还应有助于开发新的分子诊断工具，以筛选子宫内膜功能障碍，并使有针对性的治疗策略用于治疗不孕症。