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VEGF Signaling in Endothelial and Glomerular Epithelial Cells in Preeclampsia

先兆子痫中内皮细胞和肾小球上皮细胞中的 VEGF 信号转导

基本信息

批准号：
8236793
负责人：
VESNA D GAROVIC
金额：
$ 12.36万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8236793
关键词：
Affect Binding Binding Sites Blood Circulation Blood Vessels Cell Survival Cells Clinical Correlation Studies Deltastab Development Diagnostic Disease Down-Regulation Endothelial Cells Epithelial Cells Etiology Failure Functional disorder Hypertension Hypoxia Injury Intercellular Junctions Kidney Lead Mediating Modeling Morbidity - disease rate NPHS2 protein Nitric Oxide Pathogenesis Patients Placenta Plasma Pre-Eclampsia Pregnancy Premature Birth Prevention strategy Production Proteins Proteinuria Rat-1 Receptor Protein-Tyrosine Kinases Research Personnel Role Signal Transduction Testing Tight Junctions Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular Endothelium Woman angiogenesis effective therapy fetal human NOS3 protein insight mortality neonatal morbidity nephrin podocyte programs receptor slit diaphragm synaptopodin treatment strategy urinary

项目摘要

DESCRIPTION (provided by applicant): Preeclampsia is a pregnancy-specific disorder clinically characterized by hypertension and proteinuria that occurs after 20 weeks of gestation. The etiology and pathogenesis of this condition remain elusive, resulting in a failure to develop specific preventive and treatment strategies. Recent studies have provided evidence that preeclampsia is associated with elevated levels of the soluble receptor for vascular endothelial growth factor (VEGF). This soluble receptor, commonly referred to as sFlt-1 (from fmslike tyrosine kinase receptor-1), may bind and neutralize VEGF and thus decrease free VEGF levels that are required for active angiogenesis in pregnancy. We postulate that low free VEGF levels may contribute to the pathogenesis of preeclampsia in a dual fashion by causing: i) endothelial dysfunction and ii) glomerular epithelial cell (podocyte) dysregulation, leading to the two main clinical findings of preeclampsia, hypertension and proteinuria, respectively. We have demonstrated that nephrin, a slit diaphragm protein, is down-regulated in kidney sections of women who had severe preeclampsia compared to normal pregnancies. The slit diaphragm is a specialized cell-to-cell junction that connects neighboring podocytes and represents the main, size-selective filter in the kidney. In addition, we have shown that proteinuria in preeclampsia is associated with urinary loss of viable podocytes, i.e., podocyturia. In Specific Aim 1, we will study the correlations among elevated levels of plasma sFlt-1 levels, down-regulation of slit diaphragm proteins (including nephrin), and podocyturia, and explore the role of podocyturia as a possible early marker for preeclampsia. We postulate that podocyturia may occur before proteinuria and preeclampsia develop. We also hypothesize that endothelial dysfunction, a hallmark of preeclampsia that leads to hypertension, is mediated in part by low free VEGF levels that may cause a decrease in endothelial nitric oxide synthase activity and nitric oxide production. This hypothesis will be tested in Specific Aim 2. In Specific Aim 3, we will study the mechanisms by which defective VEGF signaling may down-regulate nephrin, disrupt the slit diaphragm, lead to podocyturia and, ultimately, proteinuria in preeclampsia. These studies will provide insights into basic mechanisms underlying the pathophysiology of preeclampsia, which are essential for developing more specific diagnostic and treatment approaches. Relevance: Preeclampsia affects 5% of pregnancies in the USA and remains one of the leading causes of both maternal and fetal morbidity and mortality. Currently, the only therapy is delivery, which frequently leads to premature birth and high neonatal morbidity. Development of more effective treatment strategies is critically dependent upon better understanding of underlying pathogenic mechanisms.

描述（由申请人提供）：先兆子痫是一种妊娠特异性疾病，其临床特征为妊娠 20 周后发生的高血压和蛋白尿。这种疾病的病因和发病机制仍然难以捉摸，导致无法制定具体的预防和治疗策略。最近的研究提供的证据表明，先兆子痫与血管内皮生长因子 (VEGF) 可溶性受体水平升高有关。这种可溶性受体通常称为 sFlt-1（来自 fms 样酪氨酸激酶受体-1），可以结合并中和 VEGF，从而降低妊娠期活跃血管生成所需的游离 VEGF 水平。我们推测，低游离 VEGF 水平可能以双重方式促进先兆子痫的发病，通过引起：i）内皮功能障碍和 ii）肾小球上皮细胞（足细胞）失调，分别导致先兆子痫的两个主要临床表现：高血压和蛋白尿。我们已经证明，与正常妊娠相比，患有严重先兆子痫的女性的肾脏切片中去氧肾上腺素（一种裂隙蛋白）的表达下调。狭缝隔膜是一种特殊的细胞间连接，连接相邻的足细胞，代表肾脏中主要的尺寸选择性过滤器。此外，我们还发现，先兆子痫中的蛋白尿与尿液中存活足细胞的损失（即足细胞尿）有关。在具体目标 1 中，我们将研究血浆 sFlt-1 水平升高、裂隙隔膜蛋白（包括去氧肾上腺素）下调和足细胞尿之间的相关性，并探讨足细胞尿作为先兆子痫的可能早期标志物的作用。我们假设足细胞尿可能发生在蛋白尿和先兆子痫发生之前。我们还假设，内皮功能障碍是导致高血压的先兆子痫的一个标志，部分是由低游离 VEGF 水平介导的，这可能导致内皮一氧化氮合酶活性和一氧化氮生成减少。这一假设将在特定目标 2 中得到检验。在特定目标 3 中，我们将研究缺陷 VEGF 信号传导可能下调去氧肾上腺素、破坏裂隙隔膜、导致足细胞尿并最终导致先兆子痫的蛋白尿的机制。这些研究将深入了解先兆子痫病理生理学的基本机制，这对于开发更具体的诊断和治疗方法至关重要。相关性：先兆子痫影响美国 5% 的妊娠，并且仍然是孕产妇和胎儿发病和死亡的主要原因之一。目前，唯一的治疗方法是分娩，这经常导致早产和新生儿高发病率。更有效治疗策略的制定关键取决于对潜在致病机制的更好理解。