Using genomic instability and hypoxia as predictors of placental dysfunction - PROJECT SUMMARY/ABSTRACT Preeclampsia (PE) is a hypertensive disorder that accounts for over 50,000 maternal and 500,000 fetal deaths annually worldwide, making it a leading cause of pregnancy-related mortality1–4. PE pathogenesis is multifaceted, involving abnormal placental vasculature, genetic factors, and placental ischemia-reperfusion injuries5,6 such as maternal vascular malperfusion (MVM)7. Current PE management strategies other than delivery necessitate early diagnosis and intervention3, underscoring the critical need for early diagnostic biomarkers for PE. This project investigates genomic instability in the placenta, which our preliminary data has shown to be predictive for PE and MVM in placental tissue. Due to the rapid proliferation and limited DNA repair mechanisms in villous trophoblasts, the main cell type of the placenta8, genomic instability and a high somatic mutation burden are expected features of placental development9,10. Still, confined placental mosaicism, when genetic mutations exist within the placenta but not the fetus, has been associated with PE11, highlighting the potential clinical relevance of placental genomic instability. Genomic instability can be a molecular consequence of oxidative stress12,13, and elevated levels of oxidative stress has been observed in the circulation of women with PE6. Therefore, the focus of this study is to characterize genomic instability and hypoxia during PE and MVM. In Aim 1, we will investigate genomic instability and hypoxia as biomarkers for PE and MVM. We will analyze whether genomic instability, hypoxia gene scoring, or specific somatic mutations are predictive for PE and MVM in both placental tissue and maternal circulating RNA. Congruently, we will determine whether metabolite levels of oxidative stress or other mutagens are predictive of MVM. In Aim 2, we will use patient- derived cells to capture how genomic instability changes due to both trophoblast differentiation and PE with MVM. Hi-C will how determine chromosomal rearrangements and structural variants that are relevant to DNA repair and damage affect trophoblast differentiation and pathogenesis of PE with MVM. Further, we will examine how molecular pathways may be dysregulated due to placentas with high genomic instability in placental tissue. The results of this project have the potential to inform new circulating biomarkers for early detection and therapeutic targets for PE and MVM. Additionally, this research will increase understanding of the functionality of genomic instability in the placenta, enabling future research in placental biology. My fellowship training plan includes structured training in bioinformatics and genomics, reproductive biology, scientific communication, and leadership to advance my scientific development. Research training will be guided by two bioinformatics faculty sponsors, supported by the broader UCSD placental biology research community, and supplemented by graduate student resources available at UCSD, providing a robust foundation for my goal of becoming faculty at a major research institution.
