The actions of steroid hormones on oviduct function

项目摘要/摘要 大约14%的接受辅助生殖技术(ART)的不孕不育病例是由于 输卵管功能障碍。仅在2015年，美国就进行了超过23万个艺术周期，但不到 其中30%的周期会导致怀孕。此外，表观遗传性疾病的发病率在 体外受孕的胚胎。导致不成功的主要因素和与以下方面相关的固有问题 艺术是我们对输卵管环境本质缺乏了解。改善文化媒体的尝试 然而，通过模拟输卵管环境，我们对最佳的 输卵管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 对精子迁移、受精、胚胎发育和胚胎运输至关重要。一直以来 证实卵巢衍生的类固醇激素，雌激素(E2)和孕酮(P4)，调节功能 输卵管上皮细胞的内层。然而，类固醇如何调节这些上皮细胞的功能 在怀孕建立期间为每个特定阶段量身定做的人口是不确定的。因此，在 在这项研究中，我们将开发类固醇作用及其对输卵管上皮细胞影响的时空图 在精子/胚胎运输和胚胎发育过程中。具体地说，使用鼠标模型，我们 将确定E2和P4如何调节输卵管上皮细胞的不同群体，以产生适当的 在植入前胚胎发育过程中的不同时间点发生变化的环境。我们的 中心假说是，通过E2和P4的作用对输卵管上皮进行微调可以使 输卵管创造可延展的环境，支持受精并对不断变化的新陈代谢做出反应 胚胎发育的需要。我们建议：确定1)E2和2)P4信号的作用 精子过程中输卵管分泌物或纤毛上皮细胞中的经典核受体 迁移、受精时间、植入前胚胎发育和胚胎运输。另外，3)基因 与E2和P4作用相对应的表达谱在不同区域的上皮细胞群中 输卵管和输卵管处于不同的阶段将使用小鼠模型在单细胞分辨率下定义。成功者 这些目标的实现将填补知识的根本空白，主要原因有两个。首先，这些信息将 为推动输卵管功能的分子机制提供新的见解。第二，了解哪些 细胞群在精子/胚胎运输和胚胎发育的每个阶段都会发挥作用 在艺术环境中优化文化条件所急需的信息。

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.