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Angiogenic factors, abnormal placentation and adverse pregnancy outcomes

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Preeclampsia (PE) is the most common medical complication of pregnancy and affects 5-10% of pregnant women. It is the leading cause of maternal death in developing countries and premature delivery in developed nations. PE is characterized by new onset hypertension and proteinuria occurring after 20 weeks of gestation. Currently, the only treatment for PE is delivery. Recent research has shown that certain angiogenic proteins are associated with and may be involved in the pathogenesis of PE. There is accumulating evidence that anti- angiogenic proteins (soluble fms-like tyrosine kinase-sFlt1 and soluble endoglin-sEng) are elevated, while levels of pro-angiogenic proteins (Placental Growth Factor-PIGF) are reduced in women with PE. Although sFlt1 and sEng are present in high levels in women with PE they are also present in normal pregnancies. The significance and role of these proteins in normal pregnancy and placentation is not known. Studies have shown that angiogenic imbalance may be seen as early as the first trimester of pregnancies destined to develop PE. The applicant intends to do in vitro (on cytotrophoblast cells derived from human placenta) and in vivo (on rodents) studies to investigate the role of sFlt1 and sEng on placental cytotrophoblast function. This work will not only advance the understanding of the role of angiogenic proteins in PE, but will also provide the necessary knowledge for development of drug therapies aimed at reducing levels of sFlt1 and sEng. The current standard of care for diagnosis of PE is a time-consuming clinical evaluation that may often be inaccurate because hypertension and proteinuria are not specific to PE. In addition, many women present with atypical PE, without either hypertension or proteinuria and in some women PE can develop into a life- threatening condition for the mother and her baby without any preceding signs or symptoms. This, coupled with the absence of a definitive test, leads to over diagnosis and consequently iatrogenic prematurity. Currently, there are no available biomarkers to predict PE or its adverse outcomes. Although angiogenic proteins are associated with diagnosis of PE, the clinical utility of these proteins in diagnosing PE or predicting adverse outcomes in an outpatient clinical setting is unknown. The applicant wishes to investigate whether measuring angiogenic proteins in pregnant women (as a point-of-care test) with symptoms of PE will result in more accurate and quicker diagnosis and whether these proteins correlate with pregnancy outcomes. The applicant will collect blood from pregnant women at the time they present for PE evaluation, measure their angiogenic protein levels and compare these levels with all currently available laboratory tests and clinical data used for diagnosis of PE and prediction of adverse outcomes. This work will help determine if the angiogenic protein measurement will have clinical utility that may lead to improved diagnosis of PE and better prediction of adverse outcomes related to hypertensive disorders of pregnancy. The proposed work will be performed in the laboratory of Dr. S. Ananth Karumanchi, an expert in PE biology, in the outstanding academic and research environment of Beth Israel Deaconess Medical Center and Harvard Medical School. The applicant is a Maternal Fetal Medicine specialist committed to research, understanding preeclampsia and improving maternal and fetal health. The combined expertise of mentors and collaborators provide a unique opportunity for the applicant to achieve the goals of this project and to start a career as an independent investigator.
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