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: 8240765
• 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/8240765
• 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. PUBLIC HEALTH RELEVANCE: The proposed work has immediate benefits as the measurement of angiogenic proteins, which have been implicated in causing preeclampsia, can be used in clinical settings to aid in the diagnosis of preeclampsia and predict maternal and fetal outcomes. With the exception of delivery, which often is premature, there is no treatment for preeclampsia; understanding the role of specific angiogenic proteins in both preeclampsia and healthy pregnancy is necessary for the development of novel therapies.

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的特点是妊娠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的发病有关，并可能参与其发病过程。越来越多的证据表明，PE患者的抗血管生成蛋白（可溶性纤维样酪氨酸激酶- sflt1和可溶性内啡肽- 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女性中含量很高，但在正常妊娠中也存在。这些蛋白在正常妊娠和胎盘中的意义和作用尚不清楚。研究表明，早在妊娠的前三个月就可以看到血管生成失衡，这注定会发展为PE。申请人打算进行体外（取自人胎盘的细胞滋养层细胞）和体内（啮齿动物）研究，以调查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中的作用的理解，而且还将为开发旨在降低sFlt1和sEng水平的药物治疗提供必要的知识。目前诊断PE的护理标准是一项耗时的临床评估，而且由于高血压和蛋白尿不是PE所特有的，因此往往不准确。此外，许多妇女表现为“非典型”PE，既没有高血压也没有蛋白尿，在一些妇女中，PE可以发展成危及母亲和婴儿生命的疾病，而没有任何先前的体征或症状。这一点，再加上缺乏明确的检查，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后果方面的临床应用尚不清楚。申请人希望研究在有PE症状的孕妇中测量血管生成蛋白（作为一种即时检测）是否能更准确、更快地诊断，以及这些蛋白是否与妊娠结局相关。申请人将在孕妇进行PE评估时采集其血液，测量其血管生成蛋白水平，并将这些水平与所有目前可用的实验室测试和用于PE诊断和不良后果预测的临床数据进行比较。这项工作将有助于确定血管生成蛋白测量是否具有临床应用价值，可能会导致PE的诊断改善，并更好地预测与妊娠高血压疾病相关的不良后果。拟议的工作将在体育生物学专家S. Ananth Karumanchi博士的实验室进行，在Beth Israel Deaconess医学中心和哈佛医学院优秀的学术和研究环境中进行。申请人是一名母胎医学专家，致力于研究，了解先兆子痫，改善母婴健康。导师和合作者的专业知识的结合为申请人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研究者的职业生涯。