Hypertensive Mechanisms in Preeclampsia

先兆子痫的高血压机制

• 批准号: 9037702
• 负责人: Eric Matthew George
• 金额: $ 24.88万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-08 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037702
• 关键词: Affect; Angiogenic Proteins; Antioxidants; Attention; Attenuated; Bilirubin; Binding Sites; Biological Availability; Birth; Blood; Blood Circulation; Blood Pressure; Brain Hypoxia-Ischemia; Cathepsin L; Cell surface; Cessation of life; Characteristics; Chronic; Cleaved cell; Data; Disease; Disease Management; Etiology; Exhibits; Extracellular Matrix; Extracellular Space; Goals; Health; Heparin; Heparin Binding; Human; Hyperbilirubinemia; Hypertension; Hypoxia; In Vitro; Individual; Investigation; Ischemia; KDR gene; Kidney; Literature; Mentors; Modeling; Molecular; Mothers; Mus; Newborn Infant; Oxidative Stress; Pathology; Pathway interactions; Patients; Perfusion; Phase; Placenta; Pre-Eclampsia; Pregnancy; Proteins; Proteinuria; Purinergic P1 Receptors; Rattus; Receptor Signaling; Regulation; Research; Rodent; Role; Stream; Study models; Symptoms; Techniques; Testing; Therapeutic; Tissues; United States; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vasodilator Agents; Woman; abstracting; associated symptom; base; effective therapy; endothelial dysfunction; extracellular; heme oxygenase-1; heparanase; in vivo; maternal hypertension; maternal morbidity; mortality; novel therapeutic intervention; overexpression; perinatal morbidity; pregnancy disorder; pregnant; pressure; receptor; release factor; research study; response

Project Abstract Preeclampsia remains a major health concern, affecting 5-10% of all pregnancies in the United States. It is a leading cause of maternal and perinatal morbidity and mortality. Currently, there is no effective therapy for the management of the preeclamptic patient, with the disease only remitting after birth. While the underlying mechanisms are not clear, it is believed that inadequate remodeling of the maternal vasculature leads to placental hypo-perfusion, resulting in chronic placental hypoxia/ischemia. In response the placenta releases pathogenic factors into the maternal blood stream, leading to widespread maternal endothelial dysfunction and hypertension. In recent years, a great deal of attention has been focused on the secretion of an anti- angiogenic protein, the fms-like tyrosine kinase-1 (sFlt-1). This protein is secreted into the maternal circulation by the ischemic placenta, where it directly antagonizes VEGF, and is responsible for a significant pathology associated with preeclampsia, including hypertension. While a great deal of research has focused on the pathogenic role of the protein, the molecular mechanisms which regulate its secretion remain obscure. One potential mechanism is suggested through the presence of a heparin binding site on the sFlt-1 protein and recent evidence from the literature that the switch between local retention and systemic release of sFlt-1 during normal pregnancy can be regulated by the expression of heparanase, which cleaves extracellular heparan, presumably releasing sFlt-1 into the extracellular space. This proposal seeks to test the hypothesis that the secretion of maternal sFlt-1, and thus the maternal hypertension, by the ischemic placenta is regulated by the expression of heparanase. Further, I will investigate the molecular mechanisms which regulate hypoxia- induced heparanase expression. Finally I propose that manipulation of either heparanase activity, or manipulation of the molecules regulating heparanase expression, can attenuate the hypertension produced by placental ischemia, suggesting new therapeutic approaches for the management of preeclampsia. In order to test these hypotheses, a number of in vitro and in vivo approaches will be used.

项目摘要 子痫前期仍然是一个主要的健康问题，影响到美国所有怀孕的5%-10%。这是一个 孕产妇和围产儿发病率和死亡率的主要原因。目前，还没有有效的治疗方法。 先兆子痫患者的处理，疾病在出生后才会缓解。而底层的 机制尚不清楚，据信是母体血管重塑不足导致 胎盘低血流，导致慢性胎盘缺氧/缺血。作为回应，胎盘释放 致病因子进入产妇血流，导致广泛的产妇内皮功能障碍和 高血压。近年来，抗肿瘤药物的分泌受到了极大的关注。 血管生成蛋白，FMS样酪氨酸激酶-1(sFlt-1)。这种蛋白质被分泌到母体循环中。 通过缺血胎盘，在那里它直接拮抗血管内皮生长因子，并负责一个重要的病理 与先兆子痫有关，包括高血压。虽然大量的研究都集中在 该蛋白的致病作用、调节其分泌的分子机制仍不清楚。一 可能的机制是通过在sFlt-1蛋白上存在肝素结合位点和 最近来自文献的证据表明，sFlt-1在局部滞留和全身释放之间的转换 正常妊娠可以通过乙酰肝素酶的表达来调节，乙酰肝素酶可以分解细胞外肝素， 推测是将sFlt-1释放到细胞外间隙。这一提议试图检验这样一种假设，即 缺血胎盘调节母体sFlt-1的分泌，从而引起母体高血压。 乙酰肝素酶的表达。此外，我将研究调节缺氧的分子机制- 诱导乙酰肝素酶表达。最后，我建议操纵乙酰肝素酶活性，或者 操纵调节乙酰肝素酶表达的分子，可以减轻由 胎盘缺血，为先兆子痫的治疗提供了新的治疗方法。为了 测试这些假说，将使用一些体外和体内的方法。