Kyu-Ho Lee, MD, PhD, Medical University of South Carolina
PROJECT TITLE: The Nkx2-5 Placental Transcriptome in Development and Disease
Preeclampsia effects 3-8% of all pregnancies and world wide is the leading cause of death and morbidity due to pregnancy complications, and one of the leading causes of premature birth. Understanding its basic mechanism and designing rational disease intercepts and treatments would have a tremendous impact on maternal and fetal health.
Prior studies in humans and mouse models indicated a link between expression and function of the cardiovascular developmental transcriptional regulator, Nkx2-5, and the major disease of pregnancy, preeclampsia (hypertension and proteinuria of pregnancy). Preliminary studies in a mouse model system indicated that: 1) major developmental defects occur in the placenta of Nkx2-5 (-/-) knockout mouse; and, 2) transgenically induced high expression levels of Nkx2-5 in placental trophoblasts mimicking that observed in placental tissue samples obtained from human pregnancies complicated by early onset and severe preeclampsia resulted in elevated candidate marker gene expression in placenta, and elevated levels of the VEGF antagonist and candidate preeclampsia serum marker, sFlt-1. While sFlt-1 is currently under study as a valid clinical marker of preeclampsia risk and occurrence, as well as a potential preeclampsia etiological agent, little is known about the broader mechanisms that regulate sFlt-1 production and release during placental development and pregnancy.
We have obtained and are obtaining RNA seq transcriptomic data from placental tissue of transgenic mouse model systems that either lack, or have elevated levels of Nkx2-5 gene expression in order to define genome-wide alternations in gene expression and related pathway models resulting from gain or loss of Nkx2-5 function. These insights will broaden our understanding of a candidate disease pathway for preeclampsia that will provide much needed mechanistic insight into how multiple known risk factors and confounding conditions affect the overall incidence and severity of preeclampsia.
SC INBRE Bioinformatics Pilot Project Program funded foundational RNA seq information for formulating broader placental development and disease pathways in the context of Nkx2-5 gene function, including but not limited to those related to a candidate disease mechanism hypothesis for preeclampsia.
February 9, 2018