Angiogenic factors, abnormal placentation and adverse pregnancy outcomes

描述(申请人提供)：先兆子痫(PE)是妊娠最常见的医学并发症，影响5%-10%的孕妇。它是发展中国家孕产妇死亡和发达国家早产的主要原因。PE的特点是妊娠20周后出现新发高血压和蛋白尿。目前，PE的唯一治疗方法是分娩。最近的研究表明，某些血管生成蛋白与PE的发病相关，并可能参与其发病机制。越来越多的证据表明，在PE患者中，抗血管生成蛋白(可溶性FMS样酪氨酸激酶-sFlt1和可溶性endoglin-Seng)升高，而促血管生成蛋白(胎盘生长因子-PIGF)水平降低。尽管sFlt1和Seng在PE妇女中的水平较高，但在正常妊娠中也存在。这些蛋白在正常妊娠和胎盘形成中的意义和作用尚不清楚。研究表明，血管生成失衡可能早在妊娠早期就被认为是注定要发展为PE的。申请人打算在体外(在人胎盘细胞滋养层细胞上)和体内(在啮齿动物上)研究sFlt1和Seng对胎盘细胞滋养层细胞功能的作用。这项工作不仅将促进对血管生成蛋白在PE中作用的了解，也将为旨在降低sFlt1和Seng水平的药物治疗的发展提供必要的知识。目前诊断PE的护理标准是一项耗时的临床评估，可能往往不准确，因为高血压和蛋白尿不是PE所特有的。此外，许多患有“非典型”PE的妇女没有高血压或蛋白尿，在一些妇女中，PE可在没有任何先兆或症状的情况下发展为危及母亲和婴儿生命的疾病。这一点，再加上缺乏明确的测试，导致过度诊断，从而导致医源性早产。目前，还没有可用的生物标志物来预测PE或其不良后果。尽管血管生成蛋白与PE的诊断有关，但这些蛋白在诊断PE或在门诊临床环境中预测不良结果的临床效用尚不清楚。申请人希望调查测量有PE症状的孕妇的血管生成蛋白(作为一种护理点测试)是否会导致更准确和更快的诊断，以及这些蛋白是否与妊娠结局相关。申请者将在孕妇在场进行PE评估时采集她们的血液，测量她们的血管生成蛋白水平，并将这些水平与目前用于诊断PE和预测不良结果的所有实验室测试和临床数据进行比较。这项工作将有助于确定血管生成蛋白测量是否具有临床实用价值，从而改善PE的诊断，并更好地预测与妊娠高血压疾病相关的不良结局。拟议的工作将在贝丝以色列女执事医学中心和哈佛医学院杰出的学术和研究环境下，在体育生物学专家S·阿南特·卡鲁曼奇博士的实验室进行。申请者是一名母胎医学专家，致力于研究、了解先兆子痫和改善孕产妇和胎儿健康。导师和合作者的综合专业知识为申请者提供了一个独特的机会来实现这个项目的目标，并开始作为一名独立调查人员的职业生涯。

DESCRIPTION (provided by applicant): Preeclampsia (PE) is the most common medical complication of pregnancy and affects 5-10% of pregnant women. It is the leading cause of maternal death in developing countries and premature delivery in developed nations. PE is characterized by new onset hypertension and proteinuria occurring after 20 weeks of gestation. Currently, the only treatment for PE is delivery. Recent research has shown that certain angiogenic proteins are associated with and may be involved in the pathogenesis of PE. There is accumulating evidence that anti- angiogenic proteins (soluble fms-like tyrosine kinase-sFlt1 and soluble endoglin-sEng) are elevated, while levels of pro-angiogenic proteins (Placental Growth Factor-PIGF) are reduced in women with PE. Although sFlt1 and sEng are present in high levels in women with PE they are also present in normal pregnancies. The significance and role of these proteins in normal pregnancy and placentation is not known. Studies have shown that angiogenic imbalance may be seen as early as the first trimester of pregnancies destined to develop PE. The applicant intends to do in vitro (on cytotrophoblast cells derived from human placenta) and in vivo (on rodents) studies to investigate the role of sFlt1 and sEng on placental cytotrophoblast function. This work will not only advance the understanding of the role of angiogenic proteins in PE, but will also provide the necessary knowledge for development of drug therapies aimed at reducing levels of sFlt1 and sEng. The current standard of care for diagnosis of PE is a time-consuming clinical evaluation that may often be inaccurate because hypertension and proteinuria are not specific to PE. In addition, many women present with "atypical" PE, without either hypertension or proteinuria and in some women PE can develop into a life- threatening condition for the mother and her baby without any preceding signs or symptoms. This, coupled with the absence of a definitive test, leads to over diagnosis and consequently iatrogenic prematurity. Currently, there are no available biomarkers to predict PE or its adverse outcomes. Although angiogenic proteins are associated with diagnosis of PE, the clinical utility of these proteins in diagnosing PE or predicting adverse outcomes in an outpatient clinical setting is unknown. The applicant wishes to investigate whether measuring angiogenic proteins in pregnant women (as a point-of-care test) with symptoms of PE will result in more accurate and quicker diagnosis and whether these proteins correlate with pregnancy outcomes. The applicant will collect blood from pregnant women at the time they present for PE evaluation, measure their angiogenic protein levels and compare these levels with all currently available laboratory tests and clinical data used for diagnosis of PE and prediction of adverse outcomes. This work will help determine if the angiogenic protein measurement will have clinical utility that may lead to improved diagnosis of PE and better prediction of adverse outcomes related to hypertensive disorders of pregnancy. The proposed work will be performed in the laboratory of Dr. S. Ananth Karumanchi, an expert in PE biology, in the outstanding academic and research environment of Beth Israel Deaconess Medical Center and Harvard Medical School. The applicant is a Maternal Fetal Medicine specialist committed to research, understanding preeclampsia and improving maternal and fetal health. The combined expertise of mentors and collaborators provide a unique opportunity for the applicant to achieve the goals of this project and to start a career as an independent investigator.