Project Summary/Abstract Though pregnancy in all cases harbors risk of complications, pregnancy in sickle cell disease (SCD) is associated with an exceptionally high risk of complications including preterm delivery, deep vein thrombosis, intrauterine growth restriction, preeclampsia, and intrauterine death. Women with SCD also experience higher cesarean and maternal death rates. Though the mechanistic drivers of poor pregnancy outcomes specific to SCD are not well defined, similar complications in non-SCD pregnancy are often attributed to inflammatory dysregulation and impaired vascular maintenance. These conditions are significantly elevated at baseline in SCD and highly likely to be exacerbated as pregnancy proceeds. One principal driver of such vascular impairment and inflammatory dysregulation in SCD is chronic intravascular hemolysis producing not only anemic conditions but additional release of toxic biproducts including heme. This circulating heme is detrimental to a number of vascular signaling pathways and is known to overstimulate the complement system, an innate immune responder whose activity is elevated at baseline in SCD. Under normal circumstances, well-regulated complement activation is essential to homeostasis and healthy gestation, but when overstimulated, complement activity acts to promote robust pro-inflammatory responses and local tissue degradation. In non-SCD pregnancy, complement over-activation continues to be associated with poor outcomes including early pregnancy loss, fetal growth restriction, hypertensive disorders, and preterm birth. It is further known to cause damage to trophoblast and decidual cells in the placenta. It is our belief that this heme-induced overstimulation of the complement system is at the forefront of the placental insufficiency and poor pregnancy outcomes seen in SCD. We additionally believe these outcomes can be ameliorated both indirectly through heme sequestration and directly through complement modulation. Using a well-established pre-clinical mouse model of SCD we will examine these hypotheses through the following aims. Aim 1 (K99) Characterize the effects of SCD and heme-induced complement activation on pregnancy outcomes in the humanized Townes mouse model of SCD and Aim 2 (R00) Determine if heme- and/or complement- modulation can improve pregnancy outcomes in the humanized Townes mouse model of SCD. Though poor pregnancy outcomes in SCD continue to be documented, there remains limited studies aimed at identifying underlying physiological drivers. Successful completion of these aims will provide a framework for therapeutic investigation moving forward and could establish heme-induced complement modulation as a viable candidate for further preclinical assessment with the ultimate goal of improving outcomes.