Serine Protease Corin in Pregnancy-induced Hypertension

描述（由申请人提供）：妊娠高血压会增加孕产妇和新生儿的发病率和死亡率，但其根本原因尚不清楚。Corin是一种新发现的蛋白酶。它将前心房钠尿肽（pro-ANP）转化为活性ANP，一种调节血压的心脏激素。Corin基因敲除的小鼠会患上高血压，这表明corin在维持正常血压方面的重要性。在人类中，corin变异与非洲裔美国人高血压和心脏肥大的风险增加有关。出乎意料的是，我们发现corin在小鼠妊娠子宫和胎盘中有高水平的表达，这表明corin在妊娠中的潜在作用。我们发现，corin基因敲除小鼠怀孕后血压升高，但在分娩后又恢复到怀孕前的水平。这些小鼠也有妊娠晚期蛋白尿，这是一种让人联想到人类先兆子痫的表型。因此，corin可能在子宫中发挥重要作用，以防止妊娠期高血压，corin缺乏可能有助于妊娠高血压。在这项研究中，我们将在小鼠模型中测试这一假设。在目标1中，我们计划确定子宫corin在预防妊娠高血压中的作用。在目标2中，我们计划确定子宫心钠素生产在预防妊娠高血压综合征中的作用。在目标3中，我们计划确定子宫corin介导的ANP产生在调节螺旋动脉重塑中的作用。本研究结果为妊高征的发病机制提供了新的认识。如果我们的假设得到验证，加强corin介导的途径的策略可能会发展到治疗先兆子痫患者。

DESCRIPTION (provided by applicant): Pregnancy-induced hypertension increases maternal and neonatal morbidity and mortality, but the underlying cause is poorly understood. Corin is a newly-discovered protease. It converts pro-atrial natriuretic peptide (pro-ANP) to active ANP, a cardiac hormone that regulates blood pressure. Corin knockout mice develop hypertension, indicating the importance of corin in maintaining normal blood pressure. In humans, corin variants are associated with an increased risk for hypertension and cardiac hypertrophy in African Americans. Unexpectedly, we found high levels of corin expression in the pregnant uterus and placenta in mice, suggesting a potential role of corin in pregnancy. We showed that blood pressure increased in pregnant corin null mice but returned to pre-pregnancy levels after delivery. The mice also had late gestational proteinuria, a phenotype reminiscent of preeclampsia in humans. Thus, corin may play an important role in the uterus to prevent hypertension during pregnancy and corin deficiency may contribute to pregnancy-induced hypertension. In this study, we will test this hypothesis in mouse models. In Aim 1, we plan to determine the role of uterine corin in preventing pregnancy-induced hypertension. In Aim 2, we plan to determine the role of uterine ANP production in preventing pregnancy-induced hypertension. In Aim 3, we plan to determine the role of uterine corin-mediated ANP production in regulating spiral artery remodeling. The results from our studies may provide new insights into the pathogenesis of pregnancy-induced hypertension. If our hypothesis is validated, strategies to enhance the corin-mediated pathway may be developed to treat patients with preeclampsia.