The actions of steroid hormones on oviduct function

类固醇激素对输卵管功能的作用

• 批准号: 10680793
• 负责人: Wipawee Joy Winuthayanon
• 金额: $ 22.47万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10680793
• 关键词: actions; steroid; hormones; oviduct; function

PROJECT SUMMARY/ABSTRACT Approximately 14% of infertility cases that undergo assisted reproductive technologies (ART) are due to Fallopian tube dysfunction. In 2015 alone, over 230,000 ART cycles were performed in the U.S, yet, less than 30% of those cycles resulted in pregnancy. Moreover, the incidence of epigenetic disorders is increased in in vitro-conceived embryos. A major contributing factor to the poor success and inherent problems associated with ART is our lack of understanding of the nature of the oviductal environment. Attempts to improve culture media by mimicking the oviductal environment, however, have been limited by our lack of understanding of the optimal microenvironment provided by the oviduct and how it changes during the course of preimplantation embryo development. Therefore, our long-term goal is to identify the key factors produced by each epithelial cell type that are crucial for sperm migration, fertilization, embryo development, and embryo transport. It has been established that ovarian-derived steroid hormones, estrogen (E2) and progesterone (P4), modulate the function of epithelial cell lining of the oviduct. However, how steroids modulate the function of these epithelial cell populations that are tailored for each specific stage during pregnancy establishment is undefined. As such, in this study, we will develop a spatiotemporal map of steroid actions and their effect on oviductal epithelial cells during the course of sperm/embryo transport and embryo development. Specifically, using mouse models, we will determine how E2 and P4 mediate distinct populations of epithelial cells of the oviduct to create an appropriate milieu that changes at different points in time during the course of pre-implantation embryo development. Our central hypothesis is that fine-tuning of the oviductal epithelium through the actions of E2 and P4 allows the oviduct to create a malleable environment that supports fertilization and responds to the changing metabolic needs of developing embryos. We propose to: determine the roles of 1) E2 and 2) P4 signals through their classical nuclear receptor either in the secretory or the ciliated epithelial cell of the oviduct during the sperm migration, the time of fertilization, pre-implantation embryo development, and embryo transport. Also, 3) gene expression profile corresponding to E2 and P4 action in epithelial cell populations at different regions of the oviduct and at distinct stages will be defined at a single cell resolution using mouse models. The successful completion of these aims will fill fundamental gaps in knowledge for two main reasons. First, the information will provide novel insight into the molecular mechanisms driving oviductal functions. Second, understanding which cell populations function during each stages of sperm/embryo transport and embryo development will generate much needed information to optimize culture conditions in an ART setting.

项目摘要/摘要 经历辅助生殖技术（ART）的不孕病例中约有14％是由于 输卵管功能障碍。仅在2015年，在美国就进行了230,000多个艺术周期，但不到 这些周期中有30％导致怀孕。此外，表观遗传疾病的发生率在IN中增加 体外结合的胚胎。导致成功不良和与之相关的固有问题的主要因素 艺术是我们对卵形环境的本质缺乏了解。试图改善培养基 然而，通过模仿卵形环境，我们缺乏对最佳的理解的限制 Oviduct提供的微环境及其在植入前胚胎过程中的变化 发展。因此，我们的长期目标是确定每种上皮细胞类型产生的关键因素 对于精子迁移，受精，胚胎发育和胚胎运输至关重要。它一直 确定卵巢衍生的类固醇激素，雌激素（E2）和孕酮（P4）调节功能 输卵管上皮细胞衬里。但是，类固醇如何调节这些上皮细胞的功能 在怀孕期间为每个特定阶段量身定制的人群不确定。因此，在 这项研究，我们将开发一张类固醇作用的时空图及其对产卵上皮细胞的影响 在精子/胚胎运输和胚胎发育过程中。具体来说，使用鼠标模型，我们 将确定e2和p4如何介导卵形的上皮细胞的不同种群，以创建适当的 在植入前胚胎开发过程中，在不同时间点发生变化的环境。我们的 中心假设是通过E2和P4的作用对卵形上皮进行微调允许 产卵以创建一个可延展的环境，以支持受精并响应不断变化的代谢 开发胚胎的需求。我们建议：确定1）E2和2）P4信号的作用 精子期间的分泌或纤毛上皮细胞中的经典核受体 迁移，受精时间，植入前的胚胎发育和胚胎运输。另外，3）基因 表达曲线对应于与E2和P4作用在上皮细胞种群中的E2和P4作用的不同区域 使用鼠标模型将在单个细胞分辨率下定义卵形和不同阶段。成功 这些目标的完成将填补知识的基本空白，原因有两个。首先，信息将 提供有关驱动卵巢功能的分子机制的新见解。第二，了解哪个 细胞群体在精子/胚胎传输和胚胎发育的每个阶段的功能将产生 急需的信息以优化艺术环境中的文化条件。