Biological Role of Uterine Glands in Pregnancy

子宫腺体在妊娠中的生物学作用

基本信息

批准号：
10200105
负责人：
THOMAS E SPENCER
金额：
$ 31.52万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200105
关键词：
Ablation Adenocarcinoma Adenomyosis Adult Affect Animal Model Bioinformatics Biological Biological Factors Biological Process Biology Cells ChIP-seq Characteristics Complication Computational Biology Conceptus Coupled Data Decidual Cell Reactions Defect Development Diagnosis Disease Embryo Endometrium Epithelial Estrogens Female infertility Fertility Genes Genetic Gland Goals Health Human Immunoprecipitation Implant In Vitro Infertility Knockout Mice Knowledge LIF gene Mass Spectrum Analysis Massive Parallel Sequencing Mediating Mediator of activation protein Mus NIH Program Announcements National Institute of Child Health and Human Development Natural regeneration Nature Neonatal Organ Parents Pathway interactions Physiological Physiology Pregnancy Pregnancy Maintenance Pregnancy loss Prevention Process Production Protein Microchips Publishing Recurrence Regenerative Medicine Regulation Reproductive Biology Reproductive Health Reproductive Sciences Research Research Priority Research Project Grants Role Stromal Cells Systems Biology Testing United States National Institutes of Health Uterine Gland Uterus Woman Work blastocyst chromatin immunoprecipitation conditional knockout early pregnancy loss endometriosis forkhead protein functional genomics implantation infertility treatment innovation interest knockout animal mouse model natural Blastocyst Implantation prevent reproductive outcome stem cell therapy transcriptomics uterine receptivity

项目摘要

Infertility and pregnancy loss are common health disorders affecting women. Our long-term research goal is to define critical physiological and genetic pathways that regulate uterine development, function and regeneration in order to diagnose, treat, and prevent infertility and disease problems in women. This application is specifically focused on the glands of the endometrium that are characteristic features of all uteri and critical for pregnancy. Pregnancy loss is the most common complication of human gestation, and recurrent pregnancy loss and infertility are observed in uterine gland knockout animal models. The pioneer transcription factor forkhead box A2 (FOXA2) is expressed solely in the glands of the mouse and human uterus, a critical player in uterine development and function, and implicated in a variety of diseases (infertility, adenomyosis, endometriosis, adenocarcinoma). Recent evidence strongly supports the idea that uterine glands and, by inference, their products have biological roles in uterine receptivity, blastocyst/conceptus survival and implantation, and stromal cell decidualization, which are essential processes in pregnancy establishment. However, our understanding of uterine gland and FOXA2 biology is very incomplete, particular in humans. Guided by strong preliminary data, two specific aims are proposed: (1) FOXA2 regulation of uterine physiology; and (2) impact of uterine glands on stromal cell decidualization. An integrative systems biology approach employing a combination of innovative mouse models and human endometrium will be used to discover important conserved functions of uterine glands. 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 pregnancy loss. This application specifically targets NIH program announcement PA-16-160 entitled “NIH Research Project Grant (Parent R01)” and focuses on understanding early pregnancy loss and genetic basis of idiopathic female infertility, which is a major research priority of the Fertility and Infertility Branch of the NICHD. In the long term, an increased understanding of uterine gland biology is important for diagnosis, prevention, and treatment of fertility and pregnancy problems and also for regenerative medicine therapies aimed at organ replacement and stem cell therapies to treat infertility and disease in women.

不孕症和流产是影响女性的常见健康疾病。定义调节子宫发育、功能和再生的关键生理和遗传途径为了诊断、治疗和预防女性不孕症和疾病问题。重点关注子宫内膜腺体，这是所有子宫的特征，对怀孕至关重要。流产是人类妊娠最常见的并发症，反复流产和不孕症在子宫腺体敲除动物模型中观察到先锋转录因子叉头盒 A2。 (FOXA2) 仅在小鼠和人类子宫的腺体中表达，在子宫发育中发挥着关键作用和功能，并与多种疾病（不孕症、子宫腺肌病、子宫内膜异位症、腺癌）有关。最近的证据强烈支持这样的观点，即子宫腺及其产品（由此推断）具有生物活性。在子宫容受性、囊胚/概念存活和着床以及基质细胞蜕膜化中的作用，这是怀孕建立的重要过程。然而，我们对子宫腺体的了解和了解。 FOXA2 生物学非常不完整，特别是在人类中，有两个具体目标。提出：（1）FOXA2 对子宫生理的调节；（2）子宫腺体对基质细胞的影响采用创新小鼠模型组合的综合系统生物学方法。人类子宫内膜将用于发现子宫腺体的重要保守功能。目标在概念和技术上都具有创新性，并且将通过填补该领域的空白，共同对该领域产生广泛的影响。我们在子宫生物学和流产方面的基础知识存在巨大差距。针对 NIH 计划公告 PA-16-160，标题为“NIH 研究项目补助金（父 R01）”并重点关注了解早期妊娠丢失和特发性女性不孕症的遗传基础，这是一项重大研究 NICHD 生育与不孕不育科的优先事项从长远来看，加深对这一问题的了解。子宫腺生物学对于诊断、预防和治疗生育和妊娠问题很重要以及旨在器官替代的再生医学疗法和治疗不孕症的干细胞疗法以及女性疾病。