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：
8214661
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/8214661
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 public health relevance 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）：妊娠诱发的高血压会增加母体和新生儿的发病率和死亡率，但理解的根本原因很少。科林是新发现的蛋白酶。它将促原动力纳地尿肽（Pro-ANP）转化为活性ANP，这是一种调节血压的心激素。科林敲除小鼠出现高血压，表明科林在维持正常血压方面的重要性。在人类中，科林变体与非洲裔美国人的高血压和心脏肥大的风险增加有关。出乎意料的是，我们发现小鼠怀孕子宫和胎盘的Corin表达高水平，这表明科林在怀孕中的潜在作用。我们表明，怀孕的科林无效小鼠的血压升高，但分娩后恢复到孕前水平。小鼠还患有晚期妊娠蛋白尿，这是一种让人联想到人类先兆子痫的表型。因此，科林在子宫中可能发挥重要作用，以防止怀孕期间高血压和科林缺乏症可能导致妊娠诱发的高血压。在这项研究中，我们将在小鼠模型中检验这一假设。在AIM 1中，我们计划确定子宫科林在预防妊娠引起的高血压方面的作用。在AIM 2中，我们计划确定子宫ANP产生在预防妊娠引起的高血压方面的作用。在AIM 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。我们研究的结果可能为怀孕引起的高血压的发病机理提供了新的见解。如果我们的假设得到验证，则可以制定增强科林介导的途径的策略来治疗先兆子痫的患者。公共卫生相关性：怀孕期间的高血压或高血压对母亲和胎儿都有很大的危险。该疾病发生在所有妊娠约10％中，但确切的原因尚不清楚。最近，我们从心脏中发现了一个新的分子科林，以保持正常的血压。在缺乏科林的小鼠中，怀孕期间血压升高。孕妇小鼠在尿液中的蛋白质含量也很高，这种疾病类似于妊娠诱导的高血压患者。我们的结果表明，科林对于预防怀孕期间的高血压很重要。在这项研究中，我们将尝试了解科林的工作原理，以及我们是否可以开发新的基于科林的方法来诊断和治疗怀孕期间的高血压。 1