Role of Endothelial Lipase in Atherosclerosis

内皮脂肪酶在动脉粥样硬化中的作用

• 批准号: 7344748
• 负责人: HAMID RAZZAGHI
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7344748
• 关键词: Adhesions; Affect; Atherosclerosis; Binding; Binding Sites; Biological Assay; Candidate Disease Gene; Cardiovascular Diseases; Cessation of life; Coronary artery; Coronary heart disease; DNA Sequence; Depressed mood; Disruption; Environmental Risk Factor; Enzymes; Exons; Gene Frequency; General Population; Genes; Genetic; Genetic Structures; Genetic Techniques; Heparan Sulfate Proteoglycan; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hispanics; Homodimerization; Homology Modeling; In Vitro; Individual; Inflammatory; Introns; Lead; Lipase; Lipids; Lipoprotein Binding; Metabolic Pathway; Metabolism; Missense Mutation; Molecular; Molecular Genetics; Molecular Structure; Morbidity - disease rate; Mutagenesis; Mutation; Not Hispanic or Latino; Nucleic Acid Regulatory Sequences; Numbers; Phenotype; Phospholipase; Plasma; Population; Predisposing Factor; Proteins; Publishing; Research Personnel; Risk; Risk Factors; Role; Sampling; Site; Statistical Methods; Structural Models; Structure; Substrate Specificity; Systems Analysis; Techniques; United States; Up-Regulation; Variant; Vascular Endothelium; base; cytokine; diet and exercise; gene function; genetic risk factor; glycosylation; in vivo; lipid metabolism; lipoprotein lipase; man; molecular modeling; monocyte; mortality; mutant; preference; three-dimensional modeling

The leading cause of coronary heart disease (CHD)is atherosclerosis of the coronary arteries, which is one of the most prevalent causes of morbidity and mortality in man. A major predisposing factor to atherosclerosis is low levels of high density lipoprotein-cholesterol (HDL-C). About half of the variation in HDL-C levels is due to genetic influences. Recently, a newly discovered gene, called endothelial lipase(EL), has been shown to have several unique features that make EL a prime candidate gene for low HDL-C and atherosclerosis. EL affects HDL metabolism in vivo, has high levels of phospholipase activity, is expressed by vascular endothelium, and is upregulated by inflammatory cytokines. The objectives of this project are to determine the genetic contribution of EL to variation in plasma lipid profile and to assess its role structurally and functionally. To achieve these objectives, the following specific aims will be carried out. 1) To identify and characterize mutations in the exons and intron-exon boundaries of the EL gene, molecular genetic techniques will be used in selected individuals expressing the extreme phenotype of high and low HDL-C levels. The impact of the discovered mutations on plasma lipid profile will be evaluated in two population- based samples of Hispanics (n=406) and non-Hispanic Whites (n=604) using statistical methods. 2) To build and characterize a refined 3D molecular model of EL, homology modeling techniques will be used and its structural features will be characterized. Mutant 3D models will be generated for all missense mutations identified in Aim 1 and compared with the wild type model for structural differences using molecular modeling techniques. 3) To assess the lipase activity of the mutations identified in Aim 1 and structurally assessed in Aim 2, in vitro mutagenesis, expression, and functional studies will be used. In summary, this comprehensive project will characterize EL with respect to its genetic, structure, and function in regulating plasma HDL-C levels and hence a major genetic risk factor for atherosclerosis. Understanding the molecular basis of risk factors in atherosclerosis may lead to new strategies for reducing the risk of coronary heart disease in the population.

冠心病（CHD）的主要原因是冠状动脉的动脉粥样硬化，这是一种 是人类发病和死亡的最普遍原因。一个主要的诱发因素， 动脉粥样硬化是低水平的高密度脂蛋白-胆固醇（HDL-C）。大约有一半的变异 HDL-C水平受遗传因素影响。最近，一个新发现的基因，称为内皮脂肪酶（EL）， 已显示具有几个独特的特征，使EL成为低HDL-C的主要候选基因， 动脉粥样硬化EL在体内影响HDL代谢，具有高水平的磷脂酶活性，表达为 通过血管内皮细胞，并通过炎性细胞因子上调。该项目的目标是 确定EL对血脂谱变化的遗传贡献，并从结构上评估其作用 和功能。为实现这些目标，将实现以下具体目标。1)以识别 并表征EL基因外显子和内含子-外显子边界的突变，分子遗传学 技术将用于选择的表达高和低HDL-C极端表型的个体 程度.将在两个人群中评价发现的突变对血脂谱的影响- 使用统计学方法对西班牙裔（n=406）和非西班牙裔白人（n=604）的样本进行分析。2)建立 并表征EL的精细3D分子模型，将使用同源建模技术，其 结构特征将被表征。将为所有错义突变生成突变体3D模型 在目标1中鉴定，并使用分子建模与野生型模型比较结构差异 技术. 3)评估目标1中鉴定的突变的脂肪酶活性并在结构上进行评估 目的2，体外诱变，表达和功能研究。总之，这 一个综合性的项目将从遗传、结构和调节功能方面对EL进行表征， 血浆HDL-C水平，因此是动脉粥样硬化的主要遗传危险因素。了解分子 动脉粥样硬化危险因素的基础可能导致降低冠心病风险的新策略 人口中的疾病。

项目成果

Genetic and structure-function studies of missense mutations in human endothelial lipase.

• DOI: 10.1371/journal.pone.0055716
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Razzaghi H;Tempczyk-Russell A;Haubold K;Santorico SA;Shokati T;Christians U;Churchill ME
• 通讯作者: Churchill ME