The goal of the parent grant (R01HD092419; PI: Dr. Joseph Costello) is to characterize the transcriptomic and epigenomic alterations in human placental cytotrophoblasts (CTBs) that occur in severe preeclampsia (sPE). We propose extending these analyses to CTBs isolated from placentas collected from pregnancies affected by Down Syndrome (DS) or trisomy 21 (T21). These experiments build on our finding that the maternal-fetal interface in DS has defects (e.g., impaired CTB differentiation, shallow placentation) that are similar to those observed in sPE. Thus, we propose testing the hypothesis that the similarities in the epigenetic regulators of the CTB phenotype in the two conditions will give us added insights into common mechanistic drivers. Differences could explain why relatively few women carrying T21 fetuses develop sPE (2), and shed light on placental factors that could be drivers of the wide variations observed in the DS phenotype.
Preeclampsia (PE) is a major cause of maternal and fetal, morbidity and mortality. Maternal deaths among PE and eclamptic patients can be as high as 1.8% in industrialized countries and 15% in the developing world. We will test the hypothesis that the placental epigenome and its relationship to the transcriptome hold the key to understanding the pathogenesis of sPE. The results could have significant translational potential in terms of generating novel therapeutic targets and biomarkers for predicting/diagnosing sPE using maternal blood.
