Endometrial Basis for Infertility in Women with Recurrent Implantation Failure and Pregnancy Loss

摘要 妊娠丢失是人类妊娠最常见的并发症，大约有一半发生在 自然受孕，最常见的是在怀孕的头两到三周。近年来，它已经 越来越明显的是，结构性子宫内膜功能障碍是不孕不育的重要因素 接受辅助生殖技术(ART)治疗的妇女。这个应用程序特别是 重点阐述了胚胎着床失败(EIF)、早期妊娠失败的子宫内膜起源和基础 (EPF)和复发性妊娠丢失(RPL)。中心假设是特发性的 不孕症主要源于结构性子宫内膜功能障碍，可归因于孕激素缺陷。 子宫内膜上皮、间质和免疫细胞的反应性。这项研究的目的是 开始检验这一假设，将重点放在不孕不育的妇女身上 三个月的妊娠损失。一组杰出的校外和校内调查人员， 在基础生殖生物学和翻译生殖方面具有互补性和实质性专门知识 《科学》将通过开展一项合作研究项目来解决这一假设。在美国国立卫生研究院诊所 中心，子宫内膜来自正常健康生育捐献者和不孕不育患者的队列 表型和临床定义的EIF、EPL或RPL将在门诊环境中进行活组织检查(目标1)。 将使用先进的单细胞技术来询问子宫内膜(目标1)。有机化合物将会是 用于从功能上研究子宫内膜上皮的孕酮反应(目标2)。离体 蜕膜化将用于功能性地询问激素反应和蜕膜化。 了解子宫内膜间质的容量和了解蜕膜免疫细胞的影响(目标3)。切割- 将使用EDGE基因组和转录组技术以及先进的生物信息学和数据集成 要了解细胞类型的异质性、细胞特定基因表达的差异，并识别关键 黄体酮驱动的生物通路对不孕症妇女子宫内膜功能的重要影响。 拟议的目标在概念和技术上都是创新的，共同将对 通过填补我们在子宫生物学和不孕不育基础知识方面的重大空白，我们在这一领域取得了重大进展。这 申请特别针对美国国立卫生研究院资助机会公告PAR-18-951，标题为 在美国国立卫生研究院临床中心的合作研究“，并侧重于主要研究重点 NICHD不孕不育处。这些努力将有助于我们对细胞 特发性不孕症的基础，使开发新的检测方法使临床医生能够诊断和开出处方 针对特定潜在子宫内膜功能障碍的治疗方案，并最终影响妊娠 通过个体化医学方法实现辅助受孕和自然受孕的结果。

ABSTRACT Pregnancy loss is the most common complication of human gestation, occurring in roughly one-half of natural conceptions and most frequently in the first two to three weeks of gestation. In recent years it has become apparent that constitutive endometrial dysfunction represents an important contributor to infertility in women being treated with assisted reproductive technologies (ART). This application is specifically focused on the endometrial origins and basis of embryo implantation failure (EIF), early pregnancy failure (EPF), and recurrent pregnancy loss (RPL) in ART patients. The central hypothesis is that idiopathic infertility primarily stems from constitutive endometrial dysfunction, attributable to defects in progesterone responsiveness of the endometrial epithelium and stroma as well as immune cells. The goal of this research is to begin testing this hypothesis by focusing on infertile women experiencing the continuum of first trimester pregnancy loss. A team of exceptional extramural and intramural investigators with complementary and substantial expertise in basic reproductive biology and translational reproductive sciences will address that hypothesis by conducting a collaborative research project. At the NIH Clinical Center, the endometrium from cohorts of normal healthy fertile donors and infertile patients with carefully phenotyped and clinically-defined EIF, EPL or RPL will be biopsied in an outpatient setting (Aim 1). Advanced single cell technologies will be used to interrogate the endometrium (Aim 1). Organoids will be used to functionally study progesterone responses of the endometrial epithelium (Aim 2). In vitro decidualization will be used to functionally interrogate hormone responsiveness and decidualization capacity of the endometrial stroma and understand the influence of decidual immune cells (Aim 3). Cutting- edge genomic and transcriptomic technologies and advanced bioinformatics and data integration will be used to understand cell type heterogeneity, cell-specific differences in gene expression, and discern critical progesterone-driven biological pathways important for endometrial function that are disrupted in infertile women. The proposed aims are conceptually and technically innovative and together will have a broad impact on the field by filling a substantial gap in our fundamental knowledge of uterine biology and infertility. This application specifically targets NIH funding opportunity announcement PAR-18-951 entitled “Opportunities for Collaborative Research at the NIH Clinical Center” and focuses on major research priorities of the Fertility and Infertility Branch of the NICHD. These efforts will contribute to our understanding of the cellular basis of idiopathic infertility, enable the development of new tests enabling clinicians to diagnose and prescribe regimens directed at treating specific underlying endometrial dysfunction, and ultimately impact pregnancy outcomes in assisted and natural conceptions enabled by a personalized medicine approach.