Endothelial regulation of the blood-placental barrier

Project Summary Placental vasculature is critical for the exchange of oxygen, nutrients, and waste products between maternal and fetal circulation. Failure to establish this vascular network is associated with fetal growth restriction and maternal cardiovascular pathologies. However, the signaling pathways that regulate placental vascular growth and function remain largely unknown. My long-term goal is to elucidate the cellular and molecular basis underlying placental vascular network formation and function at the blood- placental barrier, as well as how the placental endothelium affects fetal growth and maternal cardiovascular health. By utilizing a new genetic tool, the Hoxa13Cre line, that specifically targets placental vasculature but not vasculature in the embryo proper or yolk sac, I have found that placental endothelial-specific deletion of transcription regulators YAP/TAZ results in embryonic lethality and compromised placental vasculature. I propose to investigate the molecular basis for placental vascular growth and function by leveraging unique genetic tools, advanced imaging, and single-cell genomics (Aim 1). In addition, I will explore the roles of the placental endothelium in maternal-fetal exchange by combining mouse genetics and proteomic analysis (Aim 2). These lines of investigation will reveal transcriptional and epigenetic mechanisms by which placental vasculature grows and offer insights into the roles of the endothelium in the blood-placental barrier. The proposed studies complement my prior skills while acquiring new training in placental biology, single-cell technologies, and proteomics analysis to establish a strong foundation to build an independent research career. With a world-class team of mentors and collaborators with expertise in placental biology, cardiovascular metabolism, and bioinformatics to ensure exceptional guidance and a supportive, stimulating training environment at the University of Pennsylvania, I am ideally positioned to fully develop my technical skills and knowledge in placental vascular biology. Together, the proposed research and career development activities will be critical for me to develop an independent research program centered around understanding endothelial regulation in the blood-placental barrier.