Uterine Glucocorticoid Signaling: a Critical Pathway in the Establishment of Pregnancy

子宫糖皮质激素信号传导：妊娠建立的关键途径

基本信息

批准号：
10561716
负责人：
Shannon D Whirledge
金额：
$ 36.01万
依托单位：
YALE UNIVERSITY
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：
2021-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561716
关键词：
Area Biological Assay Biological Response Modifiers Birth Cell Differentiation Inhibition Cell physiology Cells Complication Critical Pathways Cytokine Signaling Cytometry Dangerousness Data Decidual Cell Decidual Cell Reactions Defect Development Disease Embryo Endometrial Endometrium Environment Etiology Event Family Fertilization Fetal Growth Retardation Fetus Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Polymorphism Genetic Transcription Glucocorticoid Receptor Glucocorticoids Goals Growth Habitual Abortion Human Image Immune Immune System Diseases Immune response Immune system Impairment Incidence Inflammatory Inflammatory Response Investigation Knockout Mice Link Macrophage Mass Spectrum Analysis Molecular Movement Mus National Institute of Child Health and Human Development Pathogenesis Pathway interactions Phenotype Population Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Maintenance Pregnancy Outcome Pregnancy Rate Pregnancy loss Process Production Race Receptor Signaling Recurrence Regulatory T-Lymphocyte Reproduction Reproductive Medicine Research Resistance Signal Pathway Signal Transduction Signaling Molecule Spontaneous abortion Stromal Cells Testing Therapeutic Intervention Time Tissues Transfection Uterus Woman Work chemokine comparison control cytokine diagnostic biomarker diagnostic tool early pregnancy early pregnancy loss failure Implantation healthy pregnancy immunoregulation implantation improved innovation knock-down maternal immune system mouse model natural Blastocyst Implantation neutrophil novel diagnostics novel therapeutic intervention pup racial population response side effect single-cell RNA sequencing therapeutic target trafficking trying to conceive

项目摘要

Pregnancy loss is a common and devastating event for women and families, and estimates suggest that more than half of all embryos are lost between fertilization and birth. A significant cause of early pregnancy loss is defective implantation, which can also set the stage for serious and potentially fatal pregnancy complications (e.g. intrauterine growth restriction and preeclampsia). Despite recent advances in reproductive medicine, most pregnancy loss is unexplained. Rates of pregnancy loss among U.S. women are on the rise. Thus, there is an urgent need to understand of cellular and molecular mechanisms governing the establishment of pregnancy, which is critical to the development of new therapeutic strategies to improve rates of implantation and pregnancy outcomes. Immune system dysregulation is thought to significantly contribute to the etiology of unexplained pregnancy loss. Glucocorticoids are master regulators of the immune system, and these transcriptional regulators represent a previously unexplored pathway contributing to the pathogenesis of pregnancy loss. We discovered that the loss of endogenous glucocorticoid signaling in the uterus causes mice to lose approximately half of all pregnancies in the first five days, similar to rates of early pregnancy loss in humans. We aim to expand our understanding of the process of implantation and the pathophysiology of early pregnancy loss by testing the central hypothesis that uterine glucocorticoid signaling is essential for the establishment and maintenance of pregnancy by directly regulating the local immune cell environment. This hypothesis is supported by the compelling preliminary data which demonstrates that (1) the regulation of genes essential to the immune response is disrupted in the uterus of uterine glucocorticoid receptor (GR) knockout mice, (2) the number of uterine macrophages, neutrophils, and regulatory T-cells are altered in the uterine GR knockout mice compared to controls, (3) GR knockdown in primary human endometrial cells inhibits the differentiation of stromal cells into decidual cells, and (4) GR polymorphisms are associated with both recurrent miscarriage and disorders of the immune system. We have proposed three discrete aims to build on these findings. In Specific Aim 1, we will determine how glucocorticoid signaling in the uterus governs immune cell trafficking. In Specific Aim 2, we will discover the GR-regulated decidualization pathways that are conserved in mouse and human endometrium. In Specific Aim 3, we will identify how a common GR polymorphism, which confers glucocorticoid resistance, alters endometrial cell function. The proposed work is innovative because our studies represent the first investigation into the local actions of glucocorticoids during the establishment of pregnancy and cross-talk between the uterus and maternal immune system. By defining these processes, our studies will generate new data to advance our understanding of early pregnancy loss and have the potential to substantially contribute toward the development of new diagnostic markers and therapeutic targets to improve pregnancy outcomes.

对于女性和家庭来说，流产是一种常见且具有破坏性的事件，据估计，超过一半的胚胎在受精和出生之间丢失。早期妊娠流产的一个重要原因是植入缺陷，这也可能为严重且可能致命的妊娠并发症（例如宫内生长受限和先兆子痫）埋下伏笔。尽管生殖医学最近取得了进展，但大多数流产仍无法解释。美国女性的流产率正在上升。因此，迫切需要了解控制妊娠建立的细胞和分子机制，这对于开发新的治疗策略以提高着床率和妊娠结局至关重要。免疫系统失调被认为是导致不明原因流产的重要原因。糖皮质激素是免疫系统的主要调节剂，这些转录调节剂代表了一种先前未探索的导致流产发病机制的途径。我们发现，子宫内源性糖皮质激素信号传导的丧失会导致小鼠在前五天内失去大约一半的妊娠，这与人类早期妊娠的丢失率相似。我们的目的是通过测试中心假设，即子宫糖皮质激素信号通过直接调节局部免疫细胞环境对于妊娠的建立和维持至关重要，从而扩大我们对着床过程和早期妊娠流产的病理生理学的理解。这一假设得到了令人信服的初步数据的支持，这些数据表明：(1) 子宫糖皮质激素受体 (GR) 敲除小鼠子宫中免疫反应必需基因的调节被破坏，(2) 子宫巨噬细胞、中性粒细胞、与对照组相比，子宫 GR 敲除小鼠中的调节性 T 细胞发生了改变。(3) 原代人子宫内膜细胞中的 GR 敲低抑制了基质细胞分化为(4) GR 多态性与复发性流产和免疫系统疾病有关。基于这些发现，我们提出了三个独立的目标。在具体目标 1 中，我们将确定子宫中的糖皮质激素信号如何控制免疫细胞运输。在具体目标 2 中，我们将发现在小鼠和人类子宫内膜中保守的 GR 调节的蜕膜化途径。在具体目标 3 中，我们将确定常见的 GR 多态性如何改变子宫内膜细胞功能，该多态性赋予糖皮质激素耐药性。拟议的工作具有创新性，因为我们的研究代表了对糖皮质激素在妊娠建立过程中的局部作用以及子宫和母体免疫系统之间的相互作用的首次调查。通过定义这些过程，我们的研究将产生新的数据，以增进我们对早期妊娠流产的理解，并有可能为开发新的诊断标记物和治疗靶点以改善妊娠结局做出重大贡献。