Role of the 5-Lipoxygenase Pathway in Atherosclerosis

5-脂氧合酶途径在动脉粥样硬化中的作用

• 批准号: 7643266
• 负责人: Hooman Allayee
• 金额: $ 50.6万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643266
• 关键词: Address; Alleles; Allergic; Amino Acid Substitution; Anabolism; Angiography; Arachidonate 5-Lipoxygenase; Arteries; Asthma; Atherosclerosis; Biochemical; Biological Assay; Blood Pressure; Breeding; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cells; Complement; Complement 2; Complementary DNA; Complex; Coronary Arteriosclerosis; Development; Diagnosis; Diagnostic tests; Disease; Dissection; Environmental Risk Factor; Enzymes; Exhibits; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Human; Hydrolase Gene; In Vitro; Individual; Inflammation; Inflammatory; Knockout Mice; Lead; Lesion; Leukocytes; Leukotriene B4; Leukotrienes; Low-Density Lipoproteins; Measures; Metabolism; Methods; Molecular; Mus; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Population; Predisposition; Proteins; Relative (related person); Research Personnel; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; Testing; Variant; atherogenesis; base; cohort; effective therapy; enzyme activity; gene interaction; genetic association; interest; leukotriene A4 hydrolase; mouse model; novel; programs; promoter; research study; trait

DESCRIPTION (provided by applicant): 1 strategy for identifying novel atherosclerosis-related genes and pathways is through a combination of studies using mouse models and human populations. Using this approach, we recently identified 5-lipoxygenase (5-LO), the rate-limiting enzyme in leukotriene (LT) biosynthesis, as a gene with dramatic effects on atherosclerosis susceptibility in mice and humans. The role of LT metabolism in the development of other allergic inflammatory diseases, most notably asthma, is already well known. This proposal, however, will address several fundamental questions that remain to be answered regarding the role of this pathway in coronary artery disease (CAD). The first aim will determine whether polymorphisms in the major genes of the 5-LO/LT pathway are associated with atherosclerosis using a large cohort of approximately 5,000 individuals on whom the diagnosis of CAD has been definitively assessed by angiography. This will not only confirm the initial observations with 5-LO, but will also determine whether genetic variation in other LT biosynthesis genes are also important for atherogenesis. The second aim will biochemically characterize the genes and polymorphisms that statistical associations in the first aim have been observed with. To complement these 2 approaches, the third aim focuses on creating additional knock out mouse models for other pathway genes. These mice will allow the genetic dissection of the pathway and the testing of specific hypotheses regarding the patho-physiological mechanism by which LTs increase atherosclerosis. 1 of the long term goals of this project are to develop genetic diagnostic tests that could be used to help identify persons at an increased risk for CAD, much in the same way that traditional risk factors, such as elevated LDL or blood pressure, are presently being used. If the 5-LO/LT pathway proves to be important for CAD, 1 of the most promising benefits could be the application of already existing drugs currently used for asthma to the management of CAD, which could lead to newer and more effective therapies.

描述（由申请人提供）：1鉴定新型动脉粥样硬化相关基因和途径的策略是使用小鼠模型和人类种群的研究结合。使用这种方法，我们最近将5-脂氧合酶（5-lo）鉴定为白细胞（LT）生物合成中的速率限制酶是对小鼠和人类动脉粥样硬化易感性产生巨大作用的基因。 LT代谢在其他过敏性炎症性疾病的发展中的作用，最著名的是哮喘。但是，该提案将解决有关该途径在冠状动脉疾病（CAD）中的作用仍有待回答的几个基本问​​题。第一个目的将确定5-LO/LT途径主要基因中的多态性是否与大约5,000个人群通过大约5,000个个体进行了动脉粥样硬化有关，他们在上面诊断了CAD的诊断已通过血管造影进行了定义评估。这不仅将用5-LO确认最初的观察结果，还将确定其他LT生物合成基因中的遗传变异是否对于动脉粥样硬化也很重要。第二个目的将在生化上表征与第一个目标中统计关联的基因和多态性的特征。为了补充这两种方法，第三个目标重点是为其他途径基因创建其他敲除鼠标模型。这些小鼠将允许对途径的遗传解剖以及有关LTS增加动脉粥样硬化的病态生理机制的特定假设的测试。该项目的长期目标中有1个是开发遗传诊断测试，这些测试可用于帮助识别有CAD风险增加的人，就像目前使用的传统风险因素（例如LDL或血压升高）一样。如果事实证明5-LO/LT途径对CAD很重要，那么最有前途的1个可能是将目前用于哮喘用于CAD管理的已经存在的药物应用于CAD的管理，这可能会导致更新，更有效的疗法。