Molecular Regulation and Role of Placenta Growth Factor

描述（由申请人提供）：许多产科并发症，包括先兆子痫和宫内生长迟缓（IUGR），这两个更重要的产妇和胎儿发病率/死亡率的原因，与滋养细胞功能障碍和胎盘血管发育异常有关。然而，导致这些功能缺陷的分子机制尚不清楚。滋养细胞通常产生强效的血管生成生长因子，胎盘生长因子（PIGF），并表达PIGF受体（flt-1），该受体以自分泌方式促进增殖和抑制细胞凋亡。体外缺氧会降低滋养细胞PIGF的表达，临床研究表明，在子痫前期，PIGF的表达显著降低。这些发现支持了我们的假设，即异常的滋养细胞产生PIGF导致了通常与子痫前期相关的血管和滋养细胞缺陷。尽管具有临床重要性，但调节滋养细胞中PIGF表达的分子机制尚不清楚。因此，以下具体目标将用于定义正常和子痫前期滋养细胞中调节PIGF基因表达的分子机制。目的1将描述滋养细胞中负责组成性高PIGF表达的调控启动子区域，并将定义滋养细胞中负责细胞类型特异性表达的区域。目的2将确定低氧张力和一氧化氮介导的转录和转录后调节机制，这些机制可以降低滋养细胞PIGF的表达。目的3将研究mRNA稳定蛋白HuR和AUF-1在调节正常和子痫前期滋养细胞中PIGF表达中的功能作用。这些研究的结果将提供关于滋养细胞组成性表达高水平PIGF的能力的关键信息，并将提供关于缺氧和一氧化氮介导的分子机制的新数据，这些机制会降低子痫前期PIGF的表达。总的来说，这些目标提供了对滋养细胞PIGF表达调节的分子机制的第一个全面的见解，这可能为逆转与灌注受损妊娠相关的抗血管生成和滋养细胞凋亡状态提供新的治疗方法。

DESCRIPTION (provided by applicant): Many obstetrical complications, including preeclampsia and intrauterine growth retardation (IUGR), two of the more significant causes of maternal and fetal morbidity/mortality, are associated with trophoblast dysfunction and aberrant placental vascular development. However, the molecular mechanisms responsible for these functional defects are poorly understood. Trophoblast normally produces the potent angiogenic growth factor, placenta growth factor (PIGF) and expresses PIGF receptors (flt-1) which function in an autocrine manner to promote proliferation and inhibit apoptosis. Trophoblast PIGF expression is uniquely reduced by hypoxia in vitro and clinical studies show that expression is significantly reduced in preeclampsia. These findings support our hypothesis that aberrant trophoblast production of PIGF contributes to the vascular and trophoblast defects commonly associated with preeclampsia. Despite this clinical importance, the molecular mechanisms regulating PIGF expression in trophoblast are not known. Accordingly, the following specific aims will be used to define the molecular mechanisms that regulate PIGF gene expression in normal and preeclamptic trophoblast. Aim 1 will characterize regulatory promoter regions responsible for constitutively high PIGF expression in trophoblast and will define regions responsible for the cell type specific expression in trophoblast. Aim 2 will determine transcriptional and post transcriptional regulatory mechanisms mediated by low oxygen tension and nitric oxide that function to decrease trophoblast PIGF expression. Aim 3 will investigate functional roles that the mRNA stabilizing proteins, HuR and AUF-1, have in regulating PIGF expression in normal and preeclamptic trophoblast. Results from these studies will provide critical information regarding the ability of trophoblast to constitutively express high levels of PIGF and will produce novel data concerning the molecular mechanisms mediated by hypoxia and nitric oxide which decrease PIGF expression during preeclampsia. Collectively, these aims provide the first comprehensive insights into the molecular mechanisms regulating trophoblast PIGF expression which may provide new therapeutic approaches to reverse the anti-angiogenic and trophoblast apoptotic states associated with perfusion compromised pregnancies.