Preeclampsia (PE) is estimated to affect 5-7% of all pregnancies in the U.S. The initiating event in PE is postulated to involve reduced placental perfusion that leads to widespread chronic immune activation and maternal vascular dysfunction. Despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent preeclampsia, and current management therapies have significant limitations. At present, the only effective treatment for preeclampsia is early delivery of the baby and placenta. Based on recent studies and on preliminary data presented in this application, we propose that the NLRP3 inflammasome is a novel therapeutic target for the treatment of PE. Recent studies have shown that NLRP3 protein expression is increased in women with PE. Our compelling preliminary data indicating that chronic administration of a NLRP3 inhibitor significantly improves blood pressure and intrauterine growth restriction in response to reduced uterine perfusion pressure (RUPP) supports the concept that modulation of the NLRP3 inflammasome may protect against the progression of PE. Additional preliminary findings demonstrate that inhibition of NLRP3 decreases T-helper 17 cells (TH17s) and cytolytic NK cell (cNK) activation, two important immune factors implicated in the pathophysiology of PE. We also provide evidence that suggest the NLRP3/caspase-1/IL-1? pathway modulate IL-33 signaling to induce immune dysfunction associated with PE in pregnant rats. Based on recent studies and on preliminary data presented in this application, we propose that inhibition of NLRP3 activation may provide novel therapeutic approaches for the treatment of PE. Our overall hypothesis is that placental ischemia activates NLRP3 and increases caspase-1/IL-1? which in turn leads to decreased IL-33 and increased TH17s and cNK activation to cause vascular and renal dysfunction, hypertension, and intrauterine growth restriction. To test this hypothesis, we will use an established animal model of PE: Reduced Uterine Perfusion Pressure (RUPP) model of placental ischemia. We will also utilize physiological and pharmacological approaches complemented with molecular, biochemical, and in vivo techniques to address vertically integrated specific aims. We are confident that our proposed studies will provide new and important information regarding the pathophysiological mechanisms linking placental ischemia and maternal hypertension and intrauterine growth restriction in PE, but more importantly help identify novel therapeutic targets for the treatment of PE.
Despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent preeclampsia (PE). At present, the only effective treatment for PE is early delivery of the baby and placenta. Based on recent studies and on preliminary data presented in this application, we propose that the NLRP3 inflammasome is a novel therapeutic target for the treatment of PE.
