Angiogenesis-related gene products in preeclampsia

先兆子痫中血管生成相关的基因产物

• 批准号: 6870361
• 负责人: S. Ananth Karumanchi
• 金额: $ 32.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870361
• 关键词: angiogenesis; cell differentiation; chemical structure function; clinical research; disease /disorder model; drug screening /evaluation; female; genetically modified animals; growth factor; growth factor receptors; human pregnant subject; immunocytochemistry; laboratory mouse; laboratory rat; morphometry; pathologic process; patient oriented research; placenta; posttranscriptional RNA processing; preeclampsia; protein metabolism; tissue /cell culture; trophoblast; vascular endothelial growth factors; women' s health

DESCRIPTION (provided by applicant): Preeclampsia (PE) is a disease, which affects 5-7% of all pregnancies and is characterized by severe hypertension, proteinuria and edema. Endothelial dysfunction plays an important role in the pathogenesis of this disorder; however, the etiology and mechanisms are still unknown. We recently found that placentas from preeclamptic patients produce an excess of a naturally occurring anti-angiogenic protein, sFIt-1 (soluble fms-like tyrosine kinase-1), resulting in increased serum levels in patients with PE as compared to normotensive pregnant women. Fit-1 is one of the tyrosine kinase receptors for vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). sFIt-1, a secreted splice variant of Fit-1 (lacking the transmembrane and cytoplasmic domains) potently antagonizes VEGF and PIGF, by preventing their binding to the cell-surface receptor. Moreover, we have found that the ratio of anti-angiogenic (sFIt-1) to pro-angiogenic (VEGF + PIGF) proteins in the maternal bloodstream at the time of delivery is substantially elevated in preeclamptic women as compared with control pregnant women. In vitro, preeclamptic serum but not normal pregnant serum induces endothelial dysfunction due to excess sFIt-1, which can be rescued by exogenous VEGF and PIGF. Finally, we have preliminary data that administration of exogenous sFIt-1 to pregnant rats induces hypertension, heavy proteinuria and glomerular endotheliosis, the classic lesion of PE. We therefore hypothesize that alteration in the angiogenic balance due to excess sFLt-1 results in the development of PE. This proposal aims to clarify the role of sFIt-1 and altered angiogenic balance in the pathogenesis of PE. We will first characterize our sFIt-1 induced animal model for PE and will test several therapeutic compounds in an attempt to find new treatment options for patients with PE. We will then elucidate the mechanisms of systemic vascular dysfunction and placental cytotrophoblast dysfunction induced by excess sFIt-1 and altered angiogenic balance using both in vitro and in vivo experiments. Finally, we will focus on studying the transcriptional and post-transcriptional regulatory mechanisms of sFIt-1 production by placental cytotrophoblasts. These focused studies will form the beginnings of a framework for understanding the role of angiogenesis-related gene products in pathogenesis of PE and for exploring novel avenues for the treatment of PE.

描述（由申请人提供）：先兆子痫（PE）是一种疾病，影响了所有妊娠的5-7％，其特征是严重的高血压，蛋白尿和水肿。内皮功能障碍在该疾病的发病机理中起重要作用。但是，病因和机制仍然未知。我们最近发现，先兆子痫患者的胎盘产生过量的自然存在的抗血管生成蛋白SFIT-1（可溶性FMS样酪氨酸激酶-1），与正常血统的孕妇相比，PE患者的血清水平升高。 FIT-1是血管内皮生长因子（VEGF）和胎盘生长因子（PIGF）的酪氨酸激酶受体之一。 SFIT-1是FIT-1的分泌剪接变体（缺乏跨膜和细胞质结构域），通过防止其与细胞表面受体的结合，可以有效地拮抗VEGF和PIGF。此外，我们发现，与对照孕妇相比，先兆子痫妇女的抗血管生成（SFIT-1）与母体血液中的抗血管生成（VEGF + PIGF）蛋白的比率显着升高。在体外，先兆子痫和不正常的孕妇血清会导致内皮功能障碍，这会导致内皮功能障碍，因为SFIT-1过多，可以通过外源性VEGF和PIGF挽救。最后，我们有初步数据，即给孕妇大鼠外源性SFIT-1的施用会诱导高血压，重蛋白尿和肾小球内皮病，这是PE的经典病变。因此，我们假设由于过量的SFLT-1导致血管生成平衡的改变导致PE的发展。该建议旨在阐明SFIT-1和变化的血管生成平衡在PE发病机理中的作用。我们将首先将我们的SFIT-1诱导动物模型定为PE，并将测试几种治疗化合物，以尝试为PE患者找到新的治疗选择。然后，我们将使用体外和体内实验都阐明全身血管功能障碍和胎盘细胞质细胞功能障碍的机制和胎盘细胞质细胞功能障碍，并改变了血管生成平衡。最后，我们将专注于研究通过胎盘胞质质细胞生产SFIT-1的转录和转录后调节机制。这些重点研究将构成一个框架的开始，以了解与血管生成相关的基因产物在PE发病机理中的作用，并探索用于治疗PE的新途径。