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

妊娠流产对妇女和家庭来说是一件常见的、毁灭性的事件，据估计，在受精和出生之间，超过一半的胚胎丢失。早孕流产的一个重要原因是植入缺陷，这也可能导致严重和潜在致命的妊娠并发症（如宫内生长受限和先兆子痫）。尽管生殖医学最近取得了进展，但大多数流产是无法解释的。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因子，这些转录调节因子代表了一个以前未被探索的途径，有助于妊娠丢失的发病机制。我们发现子宫内内源性糖皮质激素信号的缺失导致小鼠在头五天内失去了大约一半的妊娠，与人类早期妊娠的失败率相似。我们的目的是通过验证子宫糖皮质激素信号通过直接调节局部免疫细胞环境对妊娠的建立和维持至关重要的中心假设，扩大我们对着床过程和早期妊娠丢失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应答所需基因的调控被破坏；(2)与对照组相比，子宫糖皮质激素受体敲除小鼠子宫中巨噬细胞、中性粒细胞和调节性t细胞的数量发生改变；(3)人子宫内膜原代细胞中GR敲除抑制基质细胞向蜕膜细胞的分化。(4) GR多态性与复发性流产和免疫系统紊乱有关。在这些发现的基础上，我们提出了三个互不相干的目标。在特异性目标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Specific Aim 2中，我们将发现在小鼠和人类子宫内膜中保守的gr调控的去个体化途径。在特异性目标3中，我们将确定一种常见的GR多态性，它赋予糖皮质激素抗性，如何改变子宫内膜细胞功能。这项工作具有创新性，因为我们的研究首次研究了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。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志物和治疗靶点做出重大贡献，以改善妊娠结局。

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.