LIPOPROTEIN LIPASE AND PREECLAMPSIA

脂蛋白脂肪酶和先兆子痫

• 批准号: 6039516
• 负责人: Carl A Hubel
• 金额: $ 24.57万
• 依托单位: MAGEE-WOMEN'S HOSPITAL OF UPMC
• 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/6039516
• 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，使围产期死亡增加了五倍。有令人信服的证据表明，母体内皮功能障碍参与了子痫前期的发病。高甘油三酯血症、高密度脂蛋白胆固醇降低和异常小的低密度脂蛋白胆固醇颗粒是子痫前期的特征。我们提出，这些脂质异常通过氧化应激的产生促进了子痫前期患者的内皮功能障碍。脂蛋白脂酶(LPL)在清除循环中的甘油三酯方面起着至关重要的作用。LPL缺陷在心血管疾病发生发展中的重要性日益被认识到。LPL基因的几个常见变异促进了甘油三酯升高、高密度脂蛋白降低和小尺寸低密度脂蛋白的三位一体。这些功能变异体的血脂紊乱效应在怀孕期间会加剧。在我们的高加索人群中，总共有18.8%的先兆子痫患者是LPL基因的N291S或D9N编码序列变体的杂合子，而正常妊娠对照组的这一比例为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LPL基因中四种最常见的功能变异在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中的流行率。目的2是对LPL基因的编码区和启动子区域进行测序，以确定其他功能变异，然后在病例和对照中进行基因分型。我们假设LPL基因的变异在先兆子痫妇女中过度表达，而LPL基因变异是导致血脂异常的易感因素。目的3是比较按基因分型的子痫前期患者的血脂、脂质过氧化产物和内皮功能障碍的标记物。我们推测，在先兆子痫妇女中，那些携带LPL变异体的酶活性降低的人将表现出特别不利的血液学特征。在目标4中，我们将测量产后12周女性的血浆LPL酶活性，以进一步检验LPL的体质缺陷(激素和/或基因介导)与先兆子痫相关的假设。在目标5中，我们将利用LPL基因敲除小鼠，探讨LPL杂合性缺陷对妊娠期间血管内皮功能调节的影响。这一系统的方法将有助于澄清血脂异常与子痫前期发病机制之间的联系，并可能为预防或治疗这种疾病提供线索。