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.

先兆子痫是产妇死亡的主要原因，使围产期死亡增加五倍。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制。高胆固醇血症、高密度脂蛋白（HDL）胆固醇降低和异常小尺寸的低密度脂蛋白（LDL）颗粒是先兆子痫的特征性特征。我们提出这些脂质异常通过氧化应激的产生促进先兆子痫患者的内皮功能障碍。脂蛋白脂酶（LPL）在甘油三酯从循环中清除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日益被认识到。LPL基因中的几种常见变异促进甘油三酯增加、HDL胆固醇降低和小分子LDL的三联体。这些功能性变异体的血脂异常作用因妊娠而加重。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N291 S或D9 N编码序列变体的杂合子，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。我们将比较四种最常见的LPL基因功能变异在宾夕法尼亚州西部的高加索人和非洲裔美国人以及冰岛妇女中的患病率。目的2是对LPL基因的编码区和启动子区进行测序，以鉴定其他功能变体，然后对病例和对照进行基因分型。我们认为LPL基因的变异是导致血脂异常的易感基因，在先兆子痫妇女中表现过度。目的3：比较不同基因型先兆子痫患者的血脂、脂质过氧化产物和内皮功能障碍标志物。我们假设，在先兆子痫的妇女中，那些携带酶活性降低的LPL变异体的妇女将显示出特别不利的血液特征。在目标4中，我们将测量产后12周的妇女的血浆LPL酶活性，以进一步检验LPL（经尿道和/或遗传介导的）的体质缺陷与先兆子痫相关的假设。在目的5中，我们将使用LPL基因敲除小鼠，探索杂合型LPL缺陷对妊娠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澄清血脂异常和先兆子痫的发病机制之间的联系，并可能提供线索，以预防或治疗的障碍。