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

反复着床失败和妊娠失败的女性不孕的子宫内膜基础

基本信息

批准号：
10642892
负责人：
THOMAS E SPENCER
金额：
$ 65.36万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642892
关键词：
3-Dimensional ATAC-seq Assisted Reproductive Technology Bioinformatics Biological Biology Biopsy Cell Differentiation process Cells Clinic Clinical Complication Computational Biology Conceptions Data Analyses Decidua Decidual Cell Decidual Cell Reactions Defect Development Diagnosis Embryo Endometrial Endometrial Stromal Cell Endometrium Epithelial Cells Epithelium Extramural Activities FOXO1A gene Female infertility Fertility First Pregnancy Trimester Functional disorder Funding Opportunities Gene Expression Genomics Gland Goals Gynecologic Heterogeneity Hormone Responsive Human Immune In Vitro Infertility Knowledge Meta-Analysis National Institute of Child Health and Human Development Organoids Outpatients Ovarian Pathway interactions Patients Phase Phenotype Placentation Pregnancy Pregnancy Outcome Pregnancy loss Progesterone Progesterone Receptors Recurrence Regimen Reproductive Biology Reproductive Health Reproductive Sciences Research Research Personnel Research Priority Research Project Grants Resistance Sampling Signal Transduction Stromal Cells System Technology Testing Translating United States National Institutes of Health Uterus Woman Work cell type clinical center cohort data integration early pregnancy early pregnancy loss endometrial stroma endometriosis experience failure Implantation functional genomics high risk idiopathic infertility improved improved outcome innovation interest natural Blastocyst Implantation novel patient subsets personalized medicine potential biomarker pregnancy failure public health relevance recruit reproductive outcome reproductive system disorder response senescence single cell analysis single cell technology single nucleus RNA-sequencing single-cell RNA sequencing stem subfertility transcriptome transcriptome sequencing transcriptomics uterine receptivity

项目摘要

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.

抽象的流产是人类妊娠最常见的并发症，大约有一半的人会发生流产。自然受孕，最常见于妊娠的前两到三周。显而易见，子宫内膜功能障碍是导致不孕的一个重要因素该应用专门针对接受辅助生殖技术 (ART) 治疗的女性。专注于子宫内膜起源和胚胎着床失败（EIF）、早期妊娠失败的基础 (EPF) 和 ART 患者中的复发性妊娠丢失 (RPL) 的中心假设是特发性。不孕症主要是由于黄体酮缺陷导致的子宫内膜功能障碍子宫内膜上皮和基质以及免疫细胞的反应性是本研究的目标。是通过关注经历第一次连续性的不孕妇女来开始检验这一假设一个由优秀的校外和校内调查人员组成的团队基础生殖生物学和转化生殖方面的互补和丰富的专业知识科学界将通过在美国国立卫生研究院临床中心开展一项合作研究项目来解决这一假设。中心，子宫内膜来自正常健康的有生育能力的捐赠者和不孕患者的队列，经过仔细研究表型和临床定义的 EIF、EPL 或 RPL 将在门诊进行活检（目标 1）。先进的单细胞技术将用于检查子宫内膜（目标 1）。用于功能性研究子宫内膜上皮的孕酮反应（目标 2）。蜕膜化将用于功能性询问激素反应性和蜕膜化子宫内膜基质的能力并了解蜕膜免疫细胞的影响（目标 3）。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异质性、基因表达的细胞特异性差异，并辨别关键黄体酮驱动的生物途径对子宫内膜功能很重要，但在不孕女性中却被破坏。拟议的目标在概念和技术上都具有创新性，并且将共同产生广泛的影响填补了我们在子宫生物学和不孕症基础知识方面的巨大空白。申请特别针对 NIH 资助机会公告 PAR-18-951，题为“机会 NIH 临床中心的合作研究”，重点关注 NIH 临床中心的主要研究重点 NICHD 生育与不孕不育分会的这些努力将有助于我们对细胞的理解。特发性不孕症的基础，能够开发新的测试，使信徒能够诊断和开药旨在治疗特定的潜在子宫内膜功能障碍并最终影响妊娠的方案通过个性化医疗方法实现辅助和自然受孕的结果。