LIPOPROTEIN LIPASE AND PREECLAMPSIA

脂蛋白脂肪酶和先兆子痫

• 批准号: 6629064
• 负责人: Carl A Hubel
• 金额: $ 33.15万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629064
• 关键词: clinical research; developmental genetics; enzyme activity; female; fibronectins; gene expression; genetic mapping; genetic susceptibility; high density lipoproteins; human pregnant subject; human subject; insulin; laboratory mouse; lipoprotein lipase; low density lipoprotein; malonaldehyde; preeclampsia; pregnancy disorder; triglycerides; vascular cell adhesion molecule; women's health

Preeclampsia is a leading cause of maternal death and increases perinatal death five-fold. There is compelling evidence that maternal endothelial dysfunction contributes to the pathogenesis of preeclampsia. Hypertriglyceridemia, decreases in high density lipoprotein (HDL) cholesterol, and abnormally small-sized low density lipoprotein (LDL) particles are characteristic features of preeclampsia. We have proposed that these lipid abnormalities promote endothelial dysfunction in preeclampsia through the generation of oxidative stress. Lipoprotein lipase (LPL) plays a vital role in the clearance of triglycerides from the circulation. The importance of LPL defects in the development of cardiovascular disease is increasingly recognized. Several common variations in the LPL gene promote the triad of increased triglyceride, decreased HDL cholesterol, and small-sized LDL. The dyslipidemic effects of these functional variants are accentuated by pregnancy. In our Caucasian population, a sum total of 18.8% of preeclamptics are heterozygous for either the N291S or D9N coding sequence variants of the LPL gene, compared with 4.6% of normal pregnancy controls. Accordingly, Aim 1 is to test whether these observations can be generalized to other populations. We will compare the prevalence of the four most common, functional variants in the LPL gene in Caucasians and African-Americans from western Pennsylvania, and in Icelandic women. Aim 2 is to sequence the coding and promoter regions of the LPL gene to identify other functional variants, which will then be genotyped in cases and controls. We posit that variations in the LPL gene the predispose to dyslipidemia are over-represented in women with preeclampsia. Aim 3 is to compare plasma lipids, lipid peroxidation products, and markers of endothelial dysfunction in women with preeclampsia stratified by genotype. We hypothesize that, among women with preeclampsia, those carrying LPL variants with reduced enzymatic activity will display an especially adverse blood profile. In Aim 4, we will measure plasma LPL enzyme activity in women 12 weeks postpartum to further test the hypothesis that a constitutional deficiency in LPL (hormonally and/or genetically mediated) is associated with preeclampsia. In Aim 5, we will explore the effects of heterozygous LPL deficiency on endothelial regulation of vascular function during pregnancy, using the LPL knockout mouse. This systematic approach will help to clarify the link between dyslipidemia and the pathogenesis of preeclampsia and could provide clues to prevention or treatment of the disorder.

先兆子痫是孕产妇死亡的主要原因，并增加了围产期死亡五倍。有令人信服的证据表明，母体内皮功能障碍有助于先兆子痫的发病机理。高甘油三酯血症，高密度脂蛋白（HDL）胆固醇的降低，而异常小的低密度脂蛋白（LDL）颗粒则是先兆子痫的特征。我们已经提出，这些脂质异常通过产生氧化应激会促进先兆子痫的内皮功能障碍。脂蛋白脂肪酶（LPL）在循环中清除甘油三酸酯中起着至关重要的作用。 LPL缺陷在心血管疾病发展中的重要性越来越多。 LPL基因的几种常见变化促进了甘油三酸酯增加，HDL胆固醇和小型LDL的三合会。这些功能变体的血脂症效应通过妊娠而突出。在我们的高加索人群中，对于LPL基因的N291S或D9N编码序列变体而言，总计有18.8％的先兆子痫是杂合的，而正常妊娠对照组为4.6％。因此，目标1是测试这些观察结果是否可以推广到其他人群。我们将比较来自西部宾夕法尼亚州西部的高加索人和非裔美国人以及冰岛女性的LPL基因中四种最常见的功能变体的普遍性。 AIM 2是对LPL基因的编码和启动子区域进行测序，以识别其他功能变体，然后将其在病例和对照中进行基因分型。我们认为，LPL基因的变异对血脂异常的倾向在先兆子痫的女性中过高。 AIM 3是比较血浆脂质，脂质过氧化产物和内皮功能障碍的标志物在基因型分层的先兆子痫女性中。我们假设，在先兆子痫的女性中，携带具有酶活性降低的LPL变体的女性将显示出特别不良的血液谱。在AIM 4中，我们将在产后12周的女性中测量血浆LPL酶活性，以进一步检验LPL（荷尔蒙和/或遗传介导）的宪法缺陷与先兆子痫有关的假设。在AIM 5中，我们将使用LPL基因敲除小鼠探索杂合性LPL缺乏症对怀孕期间血管功能的内皮调节的影响。这种系统的方法将有助于阐明血脂异常与先兆子痫的发病机理之间的联系，并可以为预防或治疗该疾病提供线索。