This is an application for a K08 for Dr. Stephanie Gaw Valderramos, an Assistant Professor in Maternal- Fetal Medicine at the University of California at San Francisco who is establishing herself as a young investigator in multidisciplinary translational studies of placental malaria. This award will provide Dr. Valderramos with the support necessary to test the theory that placental malaria causes local inflammatory changes in the placenta, leading to dysregulation of placental function and consequently fetal growth restriction. To achieve this goal, Dr. Valderramos has assembled a mentoring team comprised of Dr. Susan Fisher, an expert in placental biology; Dr. Philip Rosenthal, an international expert in translational studies of malaria; and Dr. Margaret Feeney, an expert in pediatric immune responses to malaria. Little is known about placental development in the setting of malaria, despite fact that maternal infection is responsible for up to 35% of low birth weight infants, and that in high transmission areas, up to 70% of fetal growth restriction cases and 36% of preterm deliveries are attributable to malaria in pregnancy. In placental malaria, P. falciparum-infected red blood cells accumulate in the maternal intervillous spaces of the placenta. It is believed that the inflammatory response to infection underlies the mechanisms by which placental malaria leads to fetal growth restriction; however, the consequences of the differential inflammatory signatures in remain unexplored. Dr. Valderramos? recent work has shown that maternal and fetal macrophages have distinct gene responses to placental malaria. These differences correlate with birth weight, and depend on the mother?s pregnancy history, suggesting a new explanation for the increased susceptibility to pregnancy complications seen in first-time mothers. She will test the hypothesis that the type I interferon pathway plays an important role regulating the balance between inflammation and immunity in placental malaria, and that more severe dysregulation of this inflammatory response may have a greater negative impact on placental development and pregnancy outcome. Specifically, she will 1) apply a combination of laser capture microdissection and RNAseq approaches to placental biopsies (malaria cases vs. controls) she collected in Uganda, which will enable global transcriptional profiling of immune and other responses of individual placental cell types; and 2) test the effects of differentially expressed molecules that could impact placental development using in vitro models of this process. These studies will identify new targets for therapeutic intervention. Through a focused program of mentored training and coursework, the she will develop advanced skills in placental biology, bioinformatic analysis, translational immunology, and the design and conduct of translational studies of malaria in resource-limited settings. At the completion of this award, Dr. Valderramos will be well positioned to develop an R01 application to further define correlates and mechanisms of pathologic inflammatory responses to placental malaria.
Placental malaria is a leading global cause of morbidity and mortality from low birth weight infants, poor fetal growth, and preterm birth. In this study, we will decipher the placental innate immune response to placental malaria, evaluate its impact on fundamental placental processes, and identify correlations with clinical outcomes. These findings will increase our understanding of the mechanisms of immunologic responses to placental malaria and identify new potential strategies for the prevention and treatment of the complications from placental malaria to reduce global perinatal mortality.