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

• 批准号: 10368918
• 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
• 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/10368918
• 关键词: Area; Biological Assay; Biological Response Modifiers; Birth; Cell physiology; Cells; Complication; Consequentialism; 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; Knock-out; Knockout Mice; Link; 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; Uterus; Woman; Work; base; chemokine; cytokine; diagnostic biomarker; diagnostic tool; early pregnancy; early pregnancy loss; failure Implantation; glucocorticoid receptor alpha; healthy pregnancy; immunoregulation; implantation; improved; innovation; knock-down; macrophage; mouse model; natural Blastocyst Implantation; neutrophil; novel diagnostics; novel therapeutic intervention; pup; response; side effect; single-cell RNA sequencing; therapeutic target; trafficking; trying to conceive

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，妊娠丢失是一种常见的、毁灭性的事件，据估计，超过一半的胚胎在受精和分娩之间丢失。早期妊娠丢失的一个重要原因是植入缺陷，这也可能为严重和潜在的致命妊娠并发症(例如宫内生长受限和先兆子痫)奠定基础。尽管生殖医学最近取得了进展，但大多数妊娠损失是无法解释的。美国女性的怀孕率正在上升。因此，迫切需要了解控制妊娠形成的细胞和分子机制，这对于开发新的治疗策略以提高植入率和妊娠结局至关重要。免疫系统失调被认为是不明原因妊娠丢失的重要原因。糖皮质激素是免疫系统的主要调节器，这些转录调节器代表了一条先前未知的途径，促进了妊娠丢失的发病机制。我们发现，子宫内源性糖皮质激素信号的丢失会导致小鼠在前五天失去大约一半的妊娠，这与人类的早孕失败率相似。我们的目的是通过直接调节局部免疫细胞环境来检验子宫糖皮质激素信号对妊娠的建立和维持至关重要的中心假设，以扩大我们对着床过程和早期妊娠丢失的病理生理的理解。这一假说得到了令人信服的初步数据的支持，这些数据表明：(1)糖皮质激素受体(GR)基因敲除小鼠子宫中免疫应答所必需的基因的调控受到干扰；(2)与对照组相比，GR基因敲除小鼠子宫巨噬细胞、中性粒细胞和调节性T细胞的数量发生变化；(3)原代人类子宫内膜细胞中GR基因敲除可抑制基质细胞向蜕膜细胞的分化；(4)GR基因多态性与反复流产和免疫系统紊乱有关。我们提出了三个独立的目标，以建立在这些发现的基础上。在特定的目标1中，我们将确定子宫中的糖皮质激素信号如何调控免疫细胞的运输。在特定的目标2中，我们将发现GR调节的蜕膜形成途径，这些途径在小鼠和人类子宫内膜中是保守的。在特定的目标3中，我们将确定常见的GR基因多态性是如何改变子宫内膜细胞功能的，这种基因多态性导致糖皮质激素抵抗。这项拟议的工作具有创新性，因为我们的研究首次对糖皮质激素在怀孕期间的局部作用以及子宫和母体免疫系统之间的相互作用进行了调查。通过定义这些过程，我们的研究将产生新的数据，以促进我们对早期妊娠丢失的理解，并有可能为开发新的诊断标记物和治疗目标做出实质性贡献，以改善妊娠结局。