Angiogenic factors, abnormal placentation and adverse pregnancy outcomes

血管生成因素、异常胎盘和不良妊娠结局

• 批准号: 8441511
• 负责人: Sarosh Rana
• 金额: $ 12.99万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441511
• 关键词: Affect; Angiogenic Factor; Angiogenic Proteins; Bedside Testings; Behavior; Biological Markers; Biology; Biopsy Specimen; Blood; Blood Pressure Monitors; Blood specimen; Cells; Cessation of life; Clinical; Clinical Data; Commit; Coupled; Developed Countries; Developing Countries; Development; Diagnosis; Diagnostic; Disease; Endoglin; Environment; Evaluation; Evaluation Studies; First Pregnancy Trimester; Functional disorder; Goals; Health; Hospitalization; Hour; Human; Hypertension; In Vitro; Invaded; Israel; Kidney; Knowledge; Laboratories; Lead; Life; Literature; Liver; Measurement; Measures; Medical center; Mentors; Modeling; Molecular; Mothers; Organ; Outcome; Outpatients; Pathogenesis; Pharmacotherapy; Placenta; Placental Growth Factor; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Premature Birth; Proteins; Proteinuria; Publications; Rattus; Reporting; Research; Research Personnel; Rodent; Role; Serum; Severity of illness; Signal Transduction; Specialist; Symptoms; Syndrome; Testing; Time; Triage; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Villous; Woman; Work; adverse outcome; angiogenesis; arteriole; career; clinical Diagnosis; cytotrophoblast; fetal; fetal medicine; implantation; improved; in vivo; insight; medical complication; medical schools; neonatal morbidity; novel; novel therapeutics; outcome forecast; pregnancy disorder; premature; prevent; research clinical testing; research study; standard of care; tool; trophoblast; vasculogenesis

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.

描述（由申请人提供）：先兆子痫（PE）是妊娠最常见的医学并发症，影响5-10%的孕妇。它是发展中国家产妇死亡和发达国家早产的主要原因。PE的特征是妊娠20周后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的发病机制有关，并可能参与其中。越来越多的证据表明，PE女性中抗血管生成蛋白（可溶性fms样酪氨酸激酶-sFlt 1和可溶性内皮素-sEng）升高，而促血管生成蛋白（胎盘生长因子-PlGF）水平降低。 虽然sFlt 1和sEng在PE女性中存在高水平，但它们也存在于正常妊娠中。这些蛋白质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，血管生成不平衡可能早在注定发展PE的怀孕的前三个月就出现。申请人拟进行体外（人胎盘细胞滋养层细胞）和体内（啮齿动物）研究，以研究sFlt 1和sEng对胎盘细胞滋养层功能的作用。这项工作不仅将促进对血管生成蛋白在PE中的作用的理解，而且还将为旨在降低sFlt 1和sEng水平的药物治疗的开发提供必要的知识。 目前诊断PE的标准治疗是一项耗时的临床评估，通常可能不准确，因为高血压和蛋白尿并非PE的特异性。此外，许多女性表现为“非典型”PE，没有高血压或蛋白尿，并且在一些女性中，PE可以发展成母亲和她的婴儿的危及生命的状况，而没有任何先前的体征或症状。这一点，加上缺乏明确的测试，导致过度诊断，从而医源性早产。目前，没有可用的生物标志物来预测PE或其不良结局。虽然血管生成蛋白与PE的诊断相关，但这些蛋白在门诊诊断PE或预测不良结局方面的临床效用尚不清楚。申请方希望研究测量具有PE症状的孕妇中的血管生成蛋白（作为床旁检测）是否会导致更准确和更快的诊断，以及这些蛋白质是否与妊娠结局相关。申请方将在妊娠女性接受PE评价时采集其血液，测量其血管生成蛋白水平，并将这些水平与用于诊断PE和预测不良结局的所有现有实验室检查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性，可能会导致改善PE的诊断和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S博士的实验室进行。Ananth Karumanchi，PE生物学专家，在贝斯以色列女执事医疗中心和哈佛医学院杰出的学术和研究环境中。申请人是一位致力于研究、了解先兆子痫和改善母婴健康的母婴医学专家。导师和合作者的综合专业知识为申请人提供了一个独特的机会，以实现该项目的目标，并开始作为一个独立的调查员的职业生涯。