Mentored Patient-Oriented Research Career Development Aw

指导以患者为中心的研究职业发展Aw

• 批准号: 6087716
• 负责人: EDMUND F FUNAI
• 金额: $ 11.89万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6087716
• 关键词: biomarker; blood pressure; career; clinical research; embryo /fetus hypoxia; enzyme activity; gene expression; glutathione peroxidase; hemoglobin; human pregnant subject; immunologic assay /test; labor complications; medical complication; messenger RNA; nitric oxide; nitric oxide synthase; nitroso compounds; northern blottings; pathologic process; preeclampsia; pregnancy circulation; role model; tissue /cell culture; vascular endothelial growth factors; vascular endothelium

PROPOSAL (Adapted from the applicant's abstract): The aim of this grant application is to test the hypothesis that in normal pregnancy soluble GPx expressed by the placenta and released into the maternal compartment, catalyzes liberation of NO from S-nitrosothiols (SNOs), such as S-nitroso- glutathione (SNO-Glu). This contributes to the decrease in BP seen as a normal pregnancy progresses. The investigators propose that disturbances in placenta GPx expression or release may be responsible for the various manifestations of pre-eclampsia. In addition, a hypoxic environment, as may be found in the intervillous space early in gestation, may contribute to an increase in endothelial nitric oxide synthase (eNOS) expression, mediated through vascular endothelial growth factor (VEGF). Elevated plasma VEGF levels in the first trimester of women destined to develop pre-eclampsia may suggest an early compensatory mechanism to promote both increased angiogenesis and blood flow. They anticipate that the results of this study will extend their understanding of the pathogenesis of pre-eclampsia and contribute to strategies for early diagnosis and treatment. A comparison of GPx levels in plasma from normal pregnant, pre-eclamptic pregnant and non-pregnant women will indicate whether GPx is secreted by the placenta into the maternal circulation at levels high enough to support a role for placental GPx in the transport and bioavailability of NO. Northern blot analysis and immunoassay will be used to confirm that expression of GPx messenger ribonucleic acid (mRNA) and release of GPx protein is reduced in placentas from term pre-eclamptic pregnancies as compared to normal pregnancies. NO and SNO-Glu levels in blood from nonpregnant, normal pregnant and pre-eclamptic women will indicate whether there is a relative increase in SNO-Glu in pre-eclampsia, at the expense of bioavailable NO. SNO-hemoglobin levels in venous blood from the three groups will be compared, as one would anticipate higher levels in normal pregnant women. Preliminary data suggest that VEGF levels rise significantly in the first trimester in those patients destined to develop pre-eclampsia, and VEGF may serve as an early marker to identify those patients at risk. They will investigate potential relationships between hypoxia and the expression of VEGF, GPx and eNOS. In addition, plasma VEGF levels will be measured serially throughout gestation during normal and pre-eclamptic pregnancies, and the value of VEGF and its inhibitor, Soluble Flt-1 (sFIt-1), as early and reproducible markers of preeclampsia will be explored.

提案(改编自申请人的摘要)：这笔赠款的目的 应用是为了检验在正常妊娠中可溶的GPX的假设 通过胎盘表达并释放到母体间， 催化从S-亚硝硫醇(SNO)中释放NO，如S-亚硝基- 谷胱甘肽(SNO-Glu)。这导致了英国石油公司股价的下降 正常妊娠进展顺利。调查人员提出，骚乱在 胎盘GPX的表达或释放可能对多种 先兆子痫的表现。此外，低氧环境，就像可能的 在妊娠早期发现于绒毛间间隙，可能有助于 内皮型一氧化氮合酶(ENOS)表达上调 通过血管内皮细胞生长因子(VEGF)。血浆血管内皮生长因子升高 注定要发展为先兆子痫的妇女在怀孕前三个月的水平可能 提出一种早期代偿机制来促进血管生成的增加 和血液流动。他们预计，这项研究的结果将扩大 他们对子痫前期发病机制的理解和贡献 早期诊断和治疗的策略。 正常妊娠、子痫前期患者血浆中GPX水平的比较 孕妇和非孕妇将表明GPX是否由 胎盘进入母体循环的水平足以支持一个角色 对于胎盘中GPX的转运和生物利用度。Northern印迹 将使用分析和免疫分析来确认GPX表达 信使核糖核酸(MRNA)和GPX蛋白的释放减少 足月子痫前期妊娠胎盘与正常胎盘的比较 怀孕。正常妊娠与非妊娠孕妇血中NO和SNO-Glu水平 先兆子痫妇女将表明是否有相对增加的 Sno-Glu在子痫前期，以牺牲生物可利用的NO。SnO-血红蛋白 三组人的静脉血水平将进行比较，就像人们会做的那样 预计正常孕妇体内会有更高的水平。 初步数据显示，血管内皮生长因子水平在第一个月显著上升 在那些注定要发展为先兆子痫的患者中，三个月后，血管内皮生长因子可能 作为早期标记物来识别那些有风险的患者。他们会 探讨缺氧与血管紧张素转换酶基因表达的潜在关系 血管内皮生长因子、GPX和eNOS。此外，还将连续测量血浆血管内皮生长因子水平。 在正常和先兆子痫妊娠期间的整个妊娠过程中，以及 血管内皮生长因子及其抑制物可溶性Flt-1(SFIT-1)在早期和早期的检测价值 我们将探索先兆子痫的可重复标志物。