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: 10112938
• 负责人: Wipawee Joy Winuthayanon
• 金额: $ 35.56万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-12 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112938
• 关键词: Animals; Assisted Reproductive Technology; Atlases; Automobile Driving; Cells; Cilia; Control Animal; Culture Media; Data; Defect; Dependence; Disease; Embryo; Embryo Deaths; Embryonic Development; Ensure; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Estrogen Receptor alpha; Estrogens; Estrus; Female; Fertility; Fertilization; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Germ Cells; Goals; Heterogeneity; Human; Impairment; In Vitro; Incidence; Infertility; Knock-out; Knowledge; Mammalian Oviducts; Maps; Mediating; Metabolic; Molecular; Morphology; Mus; Nature; Nuclear Receptors; Organ; Outcome; Ovarian; Ovarian Steroid Hormone; Ovarian hormone; Play; Population; Pre-implantation Embryo Development; Pregnancy; Pregnancy Rate; Prevention; Progesterone; Protein Secretion; Regulation; Reproductive Technology; Resolution; Role; Seminal; Signal Transduction; Sperm Transport; Steroids; Technology; Testing; Time; Tube; Uterine cavity; Uterus; base; blastocyst; cell type; design; fluid flow; gamete transport; improved; in vivo; insight; migration; mouse model; novel; premature; response; single-cell RNA sequencing; spatiotemporal; sperm cell; steroid hormone; success; transcriptome

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.

项目总结/摘要 大约14%接受辅助生殖技术（ART）的不孕症病例是由于 输卵管功能障碍。仅在2015年，美国就进行了超过230，000个ART周期，然而， 其中30%的周期导致怀孕。此外，表观遗传性疾病的发病率增加， 体外受精胚胎一个主要的促成因素，穷人的成功和固有的问题， ART是我们对输卵管环境的性质缺乏了解。改进培养基的尝试 然而，通过模仿输卵管环境，由于我们缺乏对最佳环境的了解， 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子 这对精子迁移、受精、胚胎发育和胚胎运输至关重要。已经 确定了卵巢衍生的类固醇激素，雌激素（E2）和孕激素（P4），调节功能 输卵管的上皮细胞衬里。然而，类固醇如何调节这些上皮细胞的功能， 没有界定为怀孕期间每个特定阶段量身定制的人口。因此，在 本研究将建立一个类固醇激素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。具体来说，使用小鼠模型，我们 将确定E2和P4如何介导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，环境在不同时间点发生变化。我们 中心假设是通过E2和P4的作用对输卵管上皮进行微调， 输卵管创造一个可塑的环境，支持受精，并对不断变化的代谢作出反应 胚胎发育的需要。我们建议：确定1）E2和2）P4信号的作用，通过他们的 一种经典的核受体，位于精子发育过程中输卵管的分泌上皮细胞或纤毛上皮细胞中 迁移、受精时间、植入前胚胎发育和胚胎运输。（3）基因 对应于E2和P4在上皮细胞群中作用的表达谱， 将使用小鼠模型以单细胞分辨率定义输卵管和不同阶段。成功 实现这些目标将填补知识方面的根本空白，主要原因有两个。首先，信息将 为驱动输卵管功能的分子机制提供了新的见解。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发挥作用， 这是优化ART环境中培养条件所急需的信息。