Systems-Biology Analysis of Mechanisms Informing Preeclampsia-Mediated ROP Protection

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PROJECT SUMMARY Retinopathy of prematurity (ROP) is a neovascular retinal disease of preterm infants that has a significant clinical impact, accounting for up to 40% of all childhood blindness. ROP demonstrates a delayed disease onset after preterm delivery, offering a clinical window for prevention. However, we lack insight into early ROP disease mechanisms and are therefore unable to predict which infants are at greatest disease risk or prevent ROP. Maternal preeclampsia represents a natural model of ROP protection; greater understanding of the mechanisms underlying ROP protection in this setting may allow for identification of novel prediction and prevention strategies. Preeclampsia is a complex disease state thought to have multifactorial etiology, which is incompletely modeled in animals, making analysis of human preeclampsia-mediated ROP protection most translationally impactful. The purpose of this scientific work is to use a systems-biology analysis to understand the contribution of maternal, fetal and placental pathobiology to preterm infant ROP risk and mechanisms in the setting of preeclampsia. This includes disease biomarker analysis in Specific Aim1, an integrated analysis of genomic and epigenomic placental disease mechanisms in Specific Aim 2 and histologic analysis of placental protection mechanisms in Specific Aim 3. The overall goal of the integrated career development plan is to prepare the candidate to become an expert in identifying novel early ROP disease mechanisms through expertise in maternal, fetal and placental pathobiology in human populations, which represents a fundamental transition in both methodology and knowledge base for the candidate. The Training Aims complement Scientific Aims well and focus on critical training gaps. These include didactic and practical learning in 1) Advanced biologic and epidemiology statistical methods 2) Comprehensive maternal-placental pathobiology 3) Genomic and epigenomic methods, data analysis, and application and 4) Translational research team leadership. This career development and research training will be overseen by an outstanding, complementary and multidisciplinary mentoring team of researchers and mentors and will be conducted at an institution with a strong record of providing excellent support, rich training and educational resources. The candidate’s department is committed to the success of this early career clinician-scientist, providing any additional resources necessary to complete the proposed career development and research aims, and ensuring ongoing protected research time. The proposed approach is a well-supported training mechanism and future program of research that holds significant translational promise for continued contribution to improved risk stratification, ROP prevention and promotion of normal retinal vascularization. This comprehensive training will provide a strong foundation toward achieving the candidates career goal of an independent, NIH funded, program of research focused on identification of protective interventions for ROP informed by the contribution of maternal, fetal and placental pathobiology.