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.
Defects in implantation are a major cause of early pregnancy loss, can underlie serious pregnancy complications, and predispose the development of disease after birth. A lack of understanding regarding the mechanisms regulating the embryo implantation and the establishment of pregnancy represents a major barrier toward the discovery of new diagnostic tools and therapeutic intervention. The goal of this proposed project is to investigate the mechanisms by which local glucocorticoid signaling regulates the establishment and maintenance of pregnancy.
