Cardiovascular disease, preeclampsia, and microchimerism

项目总结

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading global cause of mortality in women, with significant sexual dimorphism in disease phenotypes. Reproductive events may play a role as women with preeclampsia (PE) carry an approximately 2-8 fold increased risk for CVD later in life. Although shared risk factors certainly play a role, some epidemiologic data suggests that pregnancy itself may confer some risk. One durable pregnancy- specific physiology is fetal microchimerism (FMc), a small number of fetal cells transferred to the mother during pregnancy, which are detectable for decades after delivery. Obstetric factors may influence this transfer, and cellular FMc acquisition is known to be higher in women with PE pregnancies at the time of diagnosis. Importantly, persistence of FMc cells is implicated in later-life autoimmune disease possibly due to a graft versus host response resulting in inflammatory change. A similar mechanism may be at play in CVD development, as evidenced by increased atherosclerosis and vascular dysfunction noted in women with a history of PE pregnancies. One limitation of detailed assessment of FMc in later-life adult disease is the methodology of detecting FMc itself. Current techniques rely on maternal and offspring genotyping to detect non-shared polymorphisms followed by use of customized, cell-line based quantitative PCR assays. This multi- step process is burdensome and often not feasible in post-reproductive years or using currently existing cohorts of relevant diseases, such as CVD, due to lack of family samples. Current next-generation sequencing (NGS) technologies hold promise in overcoming these limitations. The overarching goal in this proposal is to investigate a novel pathway between CVD and PE by testing the hypothesis that women with CVD and a history of PE pregnancy will more frequently harbor persistent FMc and at greater levels compared to women with uncomplicated pregnancies. Parallel to this, we will expand the applicability of an advanced NGS approach for FMc detection and quantification to catalyze important studies for understanding the implications of this unique phenomenon in CVD and other diseases. Through these combined efforts, I will gain expertise in CVD research and molecular techniques to better understand reproductive origins of disease, helping to establish my career as a translational physician scientist.