Serine Protease Corin in Pregnancy-induced Hypertension

丝氨酸蛋白酶 Corin 在妊娠高血压综合征中的作用

基本信息

批准号：
8040045
负责人：
Qingyu Wu
金额：
$ 33.36万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8040045
关键词：
African American Atrial Natriuretic Factor Blood Pressure Blood Pressure Monitors Blood flow Breeding Cardiac Cardiovascular Diseases Data Defect Diagnosis Disease Electrolytes Ensure Female Fetus Genes Genetic Polymorphism Heart Heart Hypertrophy High Prevalence Histology Hormones Human Hypertension Hypertension induced by pregnancy Kidney Knockout Mice Measures Mediating Messenger RNA Methods Molecular Mothers Mus Natriuretic Peptides Neonatal Mortality Outcome Partner in relationship Pathogenesis Pathologic Pathway interactions Patients Peptide Hydrolases Phenotype Placenta Placental Necrosis Play Pre-Eclampsia Pregnancy Pregnant Uterus Process Production Proteins Proteinuria Risk Role Serine Protease Spiral Artery of the Endometrium Staging Testing Transgenic Mice Urine Uterus Variant Work base calcification hypertensive heart disease insight male mouse model neonatal morbidity pregnant prevent trophoblast urinary

项目摘要

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. PUBLIC HEALTH RELEVANCE: High blood pressure, or hypertension, during pregnancy poses a great danger to both the mother and the fetus. The disease happens in ~10% all pregnancies, but the exact cause is not known. Recently, we discovered a new molecule, corin, from the heart that keeps normal blood pressure. In mice lacking corin, blood pressure increased during pregnancy. The pregnant mice also had high protein contents in the urine, a condition similar to patients with pregnancy-induced hypertension. Our results indicate that corin is important in preventing high blood pressure during pregnancy. In this study, we will try to understand how corin works and if we can develop new corin-based methods to diagnose and treat high blood pressure during pregnancy. 1

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，但其根本原因却知之甚少。 Corin是一种新发现的蛋白酶。它将心房钠尿肽原 (pro-ANP) 转化为活性 ANP，这是一种调节血压的心脏激素。 Corin 基因敲除小鼠会出现高血压，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，我们在小鼠怀孕子宫和胎盘中发现了高水平的corin表达，这表明corin在怀孕中的潜在作用。我们发现怀孕的 Corin 缺失小鼠的血压升高，但在分娩后恢复到怀孕前的水平。这些小鼠还患有妊娠晚期蛋白尿，这种表型让人想起人类先兆子痫。因此，corin可能在子宫中发挥重要作用，预防妊娠期高血压，并且corin缺乏可能导致妊娠高血压。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 ANP 产生在预防妊娠高血压中的作用。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。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验证，则可以开发增强 corin 介导途径的策略来治疗先兆子痫患者。公共卫生相关性：怀孕期间的高血压对母亲和胎儿都构成巨大危险。约 10% 的妊娠都会发生这种疾病，但确切原因尚不清楚。最近，我们发现了一种来自心脏的新分子，corin，它可以保持正常的血压。缺乏corin的小鼠在怀孕期间血压会升高。怀孕小鼠的尿液中蛋白质含量也很高，这与妊娠高血压患者的情况类似。我们的结果表明，corin 对于预防妊娠期高血压很重要。在这项研究中，我们将尝试了解 Corin 的工作原理，以及我们是否可以开发新的基于 Corin 的方法来诊断和治疗妊娠期高血压。 1