Mentored Patient-Oriented Research Career Development Aw

提案（改编自申请人摘要）：本基金的目的

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.