Preeclampsia (PE) is a prevalent life threatening hypertensive disease of pregnancy and remains a leading cause of maternal and neonatal morbidity and mortality. The clinical management of PE is hampered by the lack of pre-symptomatic screening, reliable diagnostic tests and effective therapy. Research proposed here is based on the novel, but compelling, hypothesis that key clinical features of preeclampsia (PE) are due to the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT1. This receptor plays a key role in regulating blood pressure and renal function, key physiological systems disturbed in PE. We have shown that greater than 95% of women with PE possess AT1 receptor agonistic autoantibodies, termed AT1- AAs, that disease severity is proportional to autoantibody titer, and that these autoantibodies cause key clinical features of PE when introduced into pregnant mice. Because these autoantibodies cause features of PE when introduced into pregnant mice it is reasonable to assume these autoantibodies cause the same clinical features in the women from whom they were isolated. Here we propose to monitor the production of AT1-AAs throughout pregnancy in a large cohort of women to determine if these autoantibodies serve as presymptomatic markers to identify women who will later develop PE or related complications (Specific Aim I). The results of research proposed under Aim I are expected to identify AT1-AA as a presymptomatic risk factor for PE and reveal a window of therapeutic opportunity to block or remove these pathogenic autoantibodies before the onset of clinical symptoms. An additional aim of proposed research (Specific Aim II) is the development of prevention or treatment strategies based on effective neutralization of the harmful autoantibodies. Experiments proposed under Aim II intend to develop autoantibody-blocking peptides to use in therapeutic strategies to prevent or treat PE. Overall, our recent research suggests that maternal autoantibodies, AT1-AAs, contribute significantly to the pathogenesis of PE. We believe that the timely detection and removal or inhibition of these autoantibodies is likely to provide significant preventative or therapeutic benefit in the medical management of PE. For maximum therapeutic benefit it will be necessary to detect (Aim I) and block (Aim II) these autoantibodies at the earliest possible time. Strategies to prevent or effectively treat preeclampsia would result in healthier babies and healthier mothers. Research proposed here is likely to contribute significantly to this goal. PUBLIC HEALTH RELEVANCE: Preeclampsia (PE) is a dangerous complication of pregnancy characterized by sudden onset hypertension, proteinuria, inflammation, and coagulopathy. The condition affects approximately 7% of first pregnancies and accounts for over 80,000 premature births each year in the US (approximately 15% of total premature births), over $4 billion in medical costs, and immeasurable human suffering. PE affects the mother's kidneys, liver and other vital organs and, if undetected or untreated, can lead to seizures (eclampsia), cerebral hemorrhage, failure in vital organs (i.e., kidney and heart) and death. By conservative estimates, each year this disease is responsible for over 75,000 maternal deaths worldwide. PE is also associated with intrauterine growth restriction, a life-threatening condition that puts the fetus at risk for many long term cardiovascular disorders. Thus, PE is a leading cause of maternal and neonatal mortality and morbidity and has an acute and long-term impact on both moms and babies. Despite intense research efforts for many years, the underlying cause of PE remains a mystery and treatment options continue to be unsatisfactory. Numerous recent publications from our laboratories support the novel, but compelling, hypothesis that key clinical features of PE are due to the action of pathogenic autoantibodies that activate the major angiotensin receptor. Here we propose to monitor the production of these pathogenic autoantibodies throughout pregnancy in a large cohort of women to determine if these autoantibodies serve as presymptomatic markers to identify women who will later develop PE or related complications. An additional aim of proposed research is to develop autoantibody-blocking peptides to use in therapeutic strategies to prevent or treat PE. Strategies to prevent or effectively treat preeclampsia would result in healthier babies and healthier mothers. Research proposed here is likely to contribute significantly to this goal.