Biological Role of Uterine Glands in Pregnancy

子宫腺体在妊娠中的生物学作用

• 批准号: 9761556
• 负责人: THOMAS E SPENCER
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 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/9761556
• 关键词: Ablation; Adenocarcinoma; 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; Epithelium; Estrogens; Female infertility; Fertility; Genes; Genetic; Gland; Goals; Health; Human; Immunoprecipitation; Implant; In Vitro; Infertility; Knock-out; 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; Outcome; Parents; Pathway interactions; Physiological; Physiology; Pregnancy; Pregnancy Maintenance; Pregnancy loss; Prevention; Process; Production; Protein Microchips; Publishing; Recurrence; Regenerative Medicine; Regulation; Reproductive Biology; Reproductive Health; Research; Research Priority; Research Project Grants; Role; Science; Stromal Cells; Systems Biology; Testing; United States National Institutes of Health; Uterine Gland; Uterus; Woman; Work; blastocyst; chromatin immunoprecipitation; early pregnancy loss; endometriosis; forkhead protein; functional genomics; implantation; infertility treatment; innovation; interest; knockout animal; mouse model; natural Blastocyst Implantation; prevent; reproductive; stem cell therapy; transcriptomics; uterine receptivity; uterus endometriosis

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.

不育和怀孕丧失是影响女性的常见健康障碍。我们的长期研究目标是 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，治疗和预防女性的不育症和疾病问题。此应用程序是专门的 专注于子宫内膜的腺体，是所有子宫的特征，对怀孕至关重要。 怀孕丧失是人类妊娠的最常见并发症，以及复发性怀孕和不育 在子宫腺体敲除动物模型中观察到。先锋转录因子叉子盒A2 （FOXA2）仅在小鼠和人子宫的腺体中表达，子宫发育的关键参与者 和功能，并在多种疾病中实施（不育，子宫腺癌，子宫内膜异位症，腺癌）。 最近的证据强烈支持了子宫网格并通过推断其产品具有生物学的想法 在子宫受体，胚泡/概念的生存和植入以及基质细胞决定性中的作用， 这是怀孕建立的基本过程。但是，我们对子宫腺的理解和 FOXA2生物学非常不完整，特别是在人类中。在强大的初步数据的指导下，两个具体的目标 提出：（1）FOXA2子宫生理学调节； （2）子宫腺对基质细胞的影响 决定。使用创新鼠标模型的组合的集成系统生物学方法 人子宫内膜将用于发现子宫腺的重要组成功能。提议 目的在概念和技术上都是创新的，通过填充一个 我们对子宫生物学和妊娠丧失的基本知识的巨大差距。该应用程序专门 针对NIH计划公告PA-16-160标题为“ NIH研究项目赠款（父母R01）”，并重点关注 了解特发性女性不育症的早期怀孕丧失和遗传基础，这是一项主要研究 NICHD的生育能力和不育分支的优先级。从长远来看，对 子宫腺生物学对于生育和妊娠问题的诊断，预防和治疗很重要 以及用于旨在器官置换和干细胞疗法的再生医学疗法，以治疗不育症 和女性疾病。