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，大约有一半的人会发生这种情况。 自然受孕，最常见于妊娠的前两到三周。近年来 很明显，组成性子宫内膜功能障碍是不孕症的重要原因， 在接受辅助生殖技术（ART）治疗的女性中。该应用程序具体为 着重探讨了胚胎着床失败（EIF）、早期妊娠失败的子宫内膜起源和基础 (EPF)和ART患者的复发性妊娠丢失（RPL）。中心假设是， 不孕症主要是由于孕激素缺陷引起的子宫内膜功能障碍 子宫内膜上皮和间质以及免疫细胞的反应性。本研究的目的 是开始测试这一假设的重点是不孕妇女经历的连续性第一 三个月妊娠丢失。一个由优秀的校外和校内调查人员组成的团队， 在基础生殖生物学和转化生殖生物学方面的互补和实质性专门知识 科学界将通过开展一个合作研究项目来解决这一假设。在NIH临床 本中心对正常健康生育供体和不孕症患者的子宫内膜进行了仔细的 表型和临床定义的EIF、EPL或RPL将在门诊环境中进行活检（目标1）。 先进的单细胞技术将用于询问子宫内膜（目标1）。类器官将是 用于功能性研究子宫内膜上皮的孕酮反应（目的2）。体外 蜕膜化将用于功能性询问激素反应性和蜕膜化 子宫内膜间质的能力，了解蜕膜免疫细胞的影响（目的3）。切割- 将使用边缘基因组和转录组技术以及先进的生物信息学和数据集成 了解细胞类型的异质性，基因表达的细胞特异性差异， 孕酮驱动的生物学途径对不孕妇女子宫内膜功能的破坏很重要。 拟议的目标在概念和技术上都具有创新性，将对以下方面产生广泛影响： 填补了我们对子宫生物学和不孕症的基础知识的巨大空白。这 申请专门针对NIH资助机会公告PAR-18-951，题为“机会 合作研究在美国国立卫生研究院临床中心”，并侧重于主要的研究重点， NICHD生育和不育分支。这些努力将有助于我们理解细胞的 根据特发性不孕症，使新的测试，使临床医生能够诊断和开处方的发展 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 通过个性化医疗方法实现辅助和自然受孕的结果。

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.