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.

抽象的怀孕丧失是人类妊娠的最常见并发症，大约发生在大约一半的自然概念，最常在妊娠前两到三周。近年来显而易见的是，构型子宫内膜功能障碍代表了不孕症的重要因素在接受辅助生殖技术（ART）治疗的妇女中。此应用程序是专门的专注于子宫内膜起源和胚胎植入衰竭（EIF）的基础，早期妊娠衰竭（EPF）和ART患者的妊娠丧失（RPL）。中心假设是特发性不孕的主要词根源于构成性子宫内膜功能障碍，归因于孕酮缺陷子宫内膜上皮和基质以及免疫细胞的反应性。这项研究的目标是开始通过专注于不育女性经历第一次连续的不育妇女来检验这一假设孕期妊娠损失。一个典型的壁外和室内调查员团队在基本生殖生物学方面的完全而实质性的专业知识，并翻译了生殖科学将通过进行协作研究项目来解决这一假设。在NIH临床上中心是正常健康肥沃供体和不育患者的子宫内膜子宫内膜表型和临床定义的EIF，EPL或RPL将在门诊环境中进行活检（AIM 1）。先进的单细胞技术将用于询问子宫内膜（AIM 1）。器官将是用于研究子宫内膜上皮的孕酮反应（AIM 2）。体外决定性化将用于在功能上询问马龙的响应能力和决定性化子宫内膜基质的能力并了解决结型免疫细胞的影响（AIM 3）。切割- 将使用边缘基因组和转录组技术以及高级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并辨别关键孕激素驱动的生物学途径对于不育女性中断的子宫内膜功能很重要。拟议的目标在概念和技术上都是创新的，将对通过填补我们对子宫生物学和不育的基本知识的巨大差距，该领域。这申请专门针对NIH资助机会公告PAR-18-951，题为“机会在NIH临床中心进行合作研究”，重点介绍 NICHD的生育和不育分支。这些努力将有助于我们对细胞的理解特发性不育症的基础，使开发新测试能够使临床医生诊断和开处方旨在治疗特定潜在子宫内膜功能障碍的方案，并最终影响怀孕个性化医学方法可以实现辅助和自然概念的结果。