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: 7178529
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7178529
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：冠心病（CHD）的主要原因是冠状动脉粥样硬化，这是人类发病率和死亡率最普遍的原因之一。动脉粥样硬化的主要诱发因素是低水平的高密度脂蛋白胆固醇（HDL-C）。大约一半的HDL-C水平的变化是由于遗传影响。最近，一个新发现的基因，称为内皮脂肪酶（EL），已被证明有几个独特的功能，使EL低HDL-C和动脉粥样硬化的主要候选基因。EL影响体内HDL代谢，具有高水平的磷脂酶活性，由血管内皮表达，并被炎性细胞因子上调。本项目的目标是确定EL的遗传贡献的血浆脂质谱的变化，并评估其结构和功能的作用。为实现这些目标，将实现以下具体目标。1)为了鉴定和表征EL基因外显子和内含子-外显子边界的突变，将在表达高和低HDL-C水平极端表型的选定个体中使用分子遗传学技术。将使用统计学方法在西班牙裔（n=406）和非西班牙裔白人（n=604）的两个基于人群的样本中评价发现的突变对血脂谱的影响。2)为了构建和表征EL的精细3D分子模型，将使用同源建模技术并表征其结构特征。将为Aim 1中鉴定的所有错义突变生成突变体3D模型，并使用分子建模技术与野生型模型比较结构差异。3)为了评估目标1中鉴定的突变和目标2中结构评估的突变的脂肪酶活性，将使用体外诱变、表达和功能研究。总之，这个综合性的项目将表征EL在其遗传、结构和调节血浆HDL-C水平方面的功能，因此是动脉粥样硬化的主要遗传危险因素。了解动脉粥样硬化危险因素的分子基础可能会导致降低人群冠心病风险的新策略。