Excellence in Research: The role of STAT5 signaling in placental dysfunction, inflammation, and fetal immune activation

The placenta is essential for a healthy pregnancy, supporting fetal development while regulating immune signals that are necessary to protect both mother and baby. One key pathway involved in this process is the JAK/STAT signaling pathway. Disruptions in this pathway can lead to harmful inflammation, placental dysfunction, and complications during pregnancy. This project aims to understand how two specific proteins in the JAK/STAT pathway, STAT2 and STAT5B, contribute to the immune processes that support a healthy pregnancy. Through an array of innovative techniques and cutting-edge human placental organoid models, this project will identify key mediators and mechanisms involved in placental development and dysfunction and will expand scientific understanding of the molecular processes that influence reproductive biology and fetal immune development. Outcomes of this research are the first step in developing therapeutics to ensure healthy pregnancies. The project will also provide hands-on training opportunities for students at various educational levels, promoting the development of necessary skills in biomedical research. Thus, this research will aid in developing the STEM workforce for the US bioeconomy. The objective of this proposal is to bridge the tremendous gap in the fundamental understanding of innate immune signaling at the placenta and to identify the mechanisms associated with placental development and immune dysfunction. The placenta as the interface between mother and fetus is a robust immunological organ and orchestrates key signals necessary to sustain a healthy pregnancy and maintain immune homeostasis necessary for immune protection and tolerance of the HLA-discordant fetus. In a normal, healthy pregnancy a delicate balance of hormones and cytokines regulates JAK/STAT signaling in immune cells at the maternal-fetal interface. This pathway is essential during pregnancy for implantation, placental development, and immunity, however increasing evidence suggests that aberrant JAK/STAT signaling at the placenta is associated with deleterious inflammation and placental dysfunction. Preliminary data suggest that STAT2 signaling promotes anti-inflammatory Th2 responses in placental cells, while STAT5B activity is associated with pro-inflammatory Th1 responses and placental dysfunction. This project will investigate the spatial distribution, activation dynamics, and downstream gene networks associated with STAT2 and STAT5B signaling in human placental cells and organoids. This innovative project will advance the understanding of innate immune signaling at the maternal-fetal interface, identify mechanisms that sustain or threaten normal placental development, and elucidate the impact of placenta immune activation on fetal immunity. Training of students and post-docs will also occur as an important means to develop the next generation of researchers for the bioeconomy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.