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

基本信息

批准号：
8927757
负责人：
Sarosh Rana
金额：
$ 6.13万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927757
关键词：
Angiogenic factors abnormal placentation adverse

项目摘要

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）是怀孕的最常见医学并发症，影响了5-10％的孕妇。这是发展中国家孕产妇死亡的主要原因和发达国家的早产。 PE的特征是妊娠20周后发生的新发作高血压和蛋白尿。目前，PE的唯一治疗方法是输送。最近的研究表明，某些血管生成蛋白与PE的发病机理有关，并且可能与PE的发病机理有关。有证据表明，抗血管生成蛋白（可溶性FMS样酪氨酸激酶-SFLT1和可溶性内ogen剂量）升高，而PE的女性降低了促血管生成蛋白（胎盘生长因子-PIGF）的水平。尽管SFLT1和SENG在PE的女性中以高水平存在于正常妊娠中。这些蛋白质在正常妊娠和胎盘中的重要性和作用尚不清楚。研究表明，血管生成的不平衡早在注定发育为PE的妊娠的头三个月就可以看到。申请人打算在体外进行（在源自人胎盘的细胞增生细胞细胞上）和体内（在啮齿动物上）研究，以研究SFLT1和SENG对胎盘细胞营养细胞功能的作用。这项工作不仅将提高人们对PE血管生成蛋白的作用的理解，而且还将为开发旨在降低SFLT1和SENG水平的药物疗法提供必要的知识。 PE诊断的当前护理标准是一种耗时的临床评估，由于高血压和蛋白尿不是PE的特定，因此通常不准确。此外，许多女性出现了“非典型” PE，没有高血压或蛋白尿，在某些女性中，PE可能会因母亲和婴儿而没有任何先前的迹象或症状而发展为生命的疾病。加上没有确定的测试的情况，导致过度诊断，从而导致医源性早产。当前，没有可用的生物标志物可以预测PE或其不良结果。尽管血管生成蛋白与PE的诊断有关，但这些蛋白质在诊断PE或预测门诊临床环境中不良结果时的临床实用性尚不清楚。申请人希望调查测量孕妇中血管生成蛋白（作为护理测试）是否具有PE症状会导致更准确，更快的诊断，以及这些蛋白质是否与妊娠结局相关。申请人将在出席PE评估时从孕妇那里收集血液，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诊断PE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将具有临床实用性，这可能会导致对PE的诊断和更好地预测与妊娠高血压疾病有关的不良后果。拟议的工作将在PE生物学专家S. Ananth Karumanchi博士的实验室中进行，该实验室在贝丝以色列执事医学中心和哈佛医学院的杰出学术和研究环境中进行。申请人是孕产妇医学专家，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人提供了一个独特的机会，以实现该项目的目标，并开始担任独立调查员的职业。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Angiogenic factors in preeclampsia: potential for diagnosis and treatment.

DOI：
10.1097/mnh.0b013e328365ad98
发表时间：
2013-11
期刊：
Current opinion in nephrology and hypertension
影响因子：
3.2
作者：
Goel A;Rana S
通讯作者：
Rana S

Plasma concentrations of soluble endoglin versus standard evaluation in patients with suspected preeclampsia.

DOI：
10.1371/journal.pone.0048259
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Rana S;Cerdeira AS;Wenger J;Salahuddin S;Lim KH;Ralston SJ;Thadhani RI;Karumanchi SA
通讯作者：
Karumanchi SA

Angiogenic factors in diagnosis, management, and research in preeclampsia.

DOI：
10.1161/hypertensionaha.113.02293
发表时间：
2014-02
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
0
作者：
Rana S;Karumanchi SA;Lindheimer MD
通讯作者：
Lindheimer MD

Epidemiology and Mechanisms of De Novo and Persistent Hypertension in the Postpartum Period.

DOI：
10.1161/circulationaha.115.015721
发表时间：
2015-11-03
期刊：
Circulation
影响因子：
37.8
作者：
Goel A;Maski MR;Bajracharya S;Wenger JB;Zhang D;Salahuddin S;Shahul SS;Thadhani R;Seely EW;Karumanchi SA;Rana S
通讯作者：
Rana S

Circulating lymphangiogenic factors in preeclampsia.