ABSTRACT Miscarriage is a major reproductive health crisis affecting 15% of all clinically confirmed pregnancies, and recurrent pregnancy loss impacts 1-2% of women. Progesterone action through the progesterone receptor in the uterus is essential for pregnancy establishment and maintenance, whereas dysregulated progesterone signaling is associated with infertility and proinflammatory gynecological diseases. Differentiation of endometrial stromal fibroblasts in the uterus, termed decidualization, is a key progesterone signaling-driven process in early pregnancy that protects and nourishes the growing embryo before formation of the placenta. For this purpose, decidualization normally suppresses inflammation, but both defective decidualization and a hyperinflammatory uterine environment are associated with pregnancy loss. To better diagnose, treat, and prevent recurrent pregnancy loss and proinflammatory gynecological diseases, a deeper understanding of how the progesterone receptor works with other factors to regulate gene expression in individual uterine cell types is needed. Serum response factor (SRF) plays important transcriptional roles in many tissue types and has been suggested as a progesterone receptor regulator in the uterus. This proposal aims to elucidate SRF's fundamental role in maintaining homeostatic uterine progesterone signaling for control of inflammation and enabling of healthy decidualization. Aim 1 will Investigate SRF's function in defining in vivo uterine cell composition and cell-specific gene regulation by first analyzing conditional Srf knockout mouse uteri over time to identify the onset of SRF deficiency-driven uterine dysregulation and then using single cell resolution RNA-sequencing and ATAC-sequencing combined with spatially resolved transcriptomics to reveal the cell type-specific molecular mechanism of the uterine dysregulation. Aim 2 will reveal the mechanism of SRF- dependent anti-inflammatory action in cultured human endometrial stromal cells (hESC) by first identifying inflammatory pathways activated by SRF deficiency in hESC and then testing targeted innate immune suppression to mitigate proinflammatory effects and restore normal decidualization. Overall, this research will uncover how SRF regulates progesterone signaling in the uterus to prevent inflammation, fibrosis, and decidualization failure. Studies on how SRF deficiency-driven inflammation leads to endometrial inflammation and infertility will serve as a model for understanding the interplay between progesterone signaling and inflammation with the goal of providing answers for recurrent miscarriage and proinflammatory gynecological diseases.