Retinopathy of prematurity (ROP) disrupts postnatal retinal vascular development within the incompletely vascularized retina of preterm infants causing up to 40% of all childhood blindness worldwide. ROP cannot be cured or prevented; treatment stops disease progression but is associated with significant ocular, visual and potentially systemic morbidity. While, postnatal oxygen supplementation underlies ROP pathogenesis, it cannot be safely modified to prevent ROP. Preeclampsia and chorioamnionitis are placental conditions which significantly correlate with postnatal vasoprotection despite oxygen stress (protection paradigms), evidenced by reduced ROP development. Mechanisms underlying placentally-mediated postnatal ROP vasoprotection are not clear; however, our group has identified the LIM homeobox 5 (LHX5) transcription factor as a placental factor which may underlie a “final common pathway” of postnatal infant vasoprotection. We have shown that preeclampsia and chorioamnionitis demonstrate placental LHX5 silencing possibly mediated by promotor methylation. LHX5 inhibits WNT signaling through direct transcriptional activation of the canonical WNT antagonist Secreted frizzled related protein 1 (sFRP1) during development and consistent with this, sFRP1 is decreased in placental tissues associated with protection paradigms. WNT signaling mediates retinal vasoprotection and reduced ROP in animal models, which is inhibited by sFRP1. Our preliminary data support a role for LHX5-sFRP1 silencing in postnatal vasoprotection via WNT signaling, finding 1) reduced plasma sFRP1 and 2) WNT signaling pathway enrichment in the systemic circulation from infants with gestational exposure to protection paradigms compared to ROP development. Our central hypothesis postulates that placental LHX5 silencing is mediated by oxygen and contributes to postnatal vasoprotection via WNT pathway enrichment in the placental, feto-placental, systemic and ocular microenvironments. We will test our central hypothesis using three specific aims designed to: 1) Determine if LHX5 mediates a vasoprotective WNT response to oxygen stress via direct transcriptional regulation of sFRP1 in retinal pigment epithelial cell- differentiated induced pluripotent stem cell models 2) Determine if LHX5 promotor methylation localizes to histologic regions typifying protection paradigms and if it is modified by oxygen stress and 3) Determine how LHX5 placental protein expression relates to protection paradigm or ROP clinical outcomes and if it correlates with WNT signaling changes within the proteome or feto-placental circulation. The rationale for the proposed research is that a mechanistic understanding of placentally-mediated postnatal vasoprotection, will provide new opportunities for the identification and development of targets for disease prevention. This proposal seeks to be the first to characterize patho-mechanisms underlying a final common pathway of placentally-mediated postnatal ROP vaso...