Serine Protease Corin in Pregnancy-induced Hypertension

描述(由申请人提供)：妊娠高血压综合征会增加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。它将心钠素前体(PRO-ANP)转化为活性ANP，这是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基因在维持正常血压方面的重要性。在人类中，Corin变异与非裔美国人患高血压和心肌肥厚的风险增加有关。出乎意料的是，我们在小鼠怀孕的子宫和胎盘中发现了高水平的Corin表达，这表明Corin在怀孕中可能起到了作用。我们发现，怀孕的Corin基因缺失的小鼠血压升高，但在分娩后恢复到怀孕前的水平。这些小鼠也有妊娠晚期蛋白尿，这是一种让人想起人类先兆子痫的表型。因此，Corin可能在子宫中起着预防妊娠期高血压的重要作用，Corin缺乏可能导致妊娠期高血压。在这项研究中，我们将在小鼠模型中检验这一假设。在目标1中，我们计划确定子宫Corin在预防妊娠高血压综合征中的作用。在目标2中，我们计划确定子宫ANP产生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构中的作用。我们的研究结果可能为妊娠高血压综合征的发病机制提供新的见解。如果我们的假设得到证实，就有可能开发出增强Corin介导的途径的策略来治疗先兆子痫患者。

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.