Preeclampsia is a leading cause of maternal death and a major contributor to maternal and perinatal morbidity. The molecular basis for the pathogenesis of preeclampsia is poorly understood. However, significant insight has been provided by recent evidence indicating that women with preeclampsia have autoantibodies capable of activating the angiotensin receptor AT1. These AT1 receptor agonistic autoantibodies, termed AT1-AAs, may account for many features of preeclampsia. The following specific aims are designed to evaluate the functional importance of AT1-AAs in the pathophysiology of preeclampsia, the potential of autoantibody blocking therapies for the treatment of preeclampsia and the mechanism by which these autoantibodies activate the AT1 receptor. Associated with each aim is a list of specific questions to be addressed.
AIM I. Evaluate the potential contribution of AT1-AAs to the pathophysiology of preeclampsia. A. How do AT1-AAs contribute to the maternal syndrome? B. Do AT1-AAs contribute to the placental abnormalities associated with preeclampsia? C. Do AT1-AAs contribute to fetal growth retardation? D. What pathophysiological consequences of AT1-AAs are independent of pregnancy? AIM II. Examine therapeutic strategies based on blocking autoantibody-induced AT1 receptor activation. A. What epitope peptides are most effective at blocking autoantibody-induced AT1 receptor activation? B. How effective are therapeutic strategies based on the use of antibody blocking epitope peptides? C. Can autoantibody-induced features of preeclampsia be reversed by antibody blocking epitope peptides? AIM III. Determine the mechanism of autoantibody-induced AT1 receptor activation. A. Is AT1 receptor activation the result of AT1-AA-induced AT1 receptor homodimerization? B. Does antibody binding result in prolonged AT1 receptor activation? C. Do AT1-AAs contribute to AT1 receptor heterodimerization with the bradykinin B2 receptor? If AT1-AAs play a major role in the pathophysiology of preeclampsia, as we hypothesize, it should be possible to block this antibody response and in this way either forestall or prevent the onset of this disease. Our research is likely to contribute significantly to these goals. Preeclampsia is a serious hypertensive condition of pregnancy that is a leading cause of maternal and neonatal mortality and morbidity in the United States and the world. Research proposed here tests the hypothesis that autoantibodies present in women with preeclampsia contribute to many features of the condition.
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