Mentored Patient-Oriented Research Career Development Aw

提案（改编自申请人的摘要）：本补助金的目的 应用程序是测试假设，在正常妊娠可溶性GPx 由胎盘表达并释放到母体腔室中， 催化NO从S-亚硝基硫醇（SNO），如S-亚硝基- 谷胱甘肽（SNO-Glu）。 这有助于降低血压， 正常的怀孕过程。 调查人员认为， 胎盘GPx的表达或释放可能是导致 先兆子痫的表现。 此外，低氧环境，如可能 在妊娠早期的绒毛间隙中发现，可能有助于 内皮型一氧化氮合酶（eNOS）表达增加，介导 通过血管内皮生长因子（VEGF）。 血浆VEGF升高 注定要发展为先兆子痫的妇女在头三个月的水平可能 提示早期代偿机制促进血管生成增加 和血液流动。 他们预计，这项研究的结果将扩大 他们对先兆子痫发病机制的理解， 早期诊断和治疗策略。 正常妊娠与子痫前期患者血浆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高到足以支持一个角色 胎盘GPx在NO的转运和生物利用度中的作用。北方印迹杂交 将使用分析和免疫测定来确认GPx表达 信使核糖核酸（mRNA）和GPx蛋白的释放减少， 与正常妊娠相比， 怀孕。 非孕妇女、正常妊娠妇女血中NO和SNO-Glu水平 和先兆子痫的妇女将表明是否有相对增加， 先兆子痫中的SNO-Glu，以生物可利用的NO为代价。 将比较三组静脉血中的水平， 在正常孕妇中的含量会更高。 初步数据表明，VEGF水平在第一次 在那些注定发展为先兆子痫的患者中，VEGF可能 作为早期标记，以识别那些有风险的患者。 他们将 研究缺氧和表达之间的潜在关系， VEGF、GPx和eNOS。 此外，将连续测量血浆VEGF水平 在正常妊娠和先兆子痫妊娠期间， VEGF及其抑制剂可溶性Flt-1（sFIt-1）在早期和 将探索先兆子痫的可重复标记。

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.