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: 7112247
• 负责人: Hooman Allayee
• 金额: $ 51.15万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112247
• 关键词: atherosclerosis; cardiovascular disorder risk; clinical research; coronary disorder; eicosanoid metabolism; genetic polymorphism; genetic susceptibility; human data; human genetic material tag; laboratory mouse; leukotrienes; lipoxygenase; pathologic process; patient /disease registry

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）：鉴定新型动脉粥样硬化相关基因和途径的策略是通过小鼠模型和人类群体的研究相结合。利用这种方法，我们最近发现了5-脂氧合酶（5-LO），白三烯（LT）生物合成中的限速酶，是一个对小鼠和人类动脉粥样硬化易感性有显著影响的基因。LT代谢在其他过敏性炎症疾病（尤其是哮喘）发展中的作用已经为人所知。然而，这一建议将解决有关该途径在冠状动脉疾病（CAD）中的作用的几个基本问题。第一个目的是确定5-LO/LT通路主要基因的多态性是否与动脉粥样硬化有关，研究人员对大约5000名通过血管造影确诊冠心病的患者进行了研究。这不仅将证实5-LO的初步观察结果，还将确定其他LT生物合成基因的遗传变异是否对动脉粥样硬化也很重要。第二个目标将生物化学特征的基因和多态性，统计关联在第一个目标已被观察到。为了补充这两种方法，第三个目标侧重于为其他途径基因创建额外的敲除小鼠模型。这些小鼠将允许对该途径进行遗传解剖，并测试有关LTs增加动脉粥样硬化的病理生理机制的特定假设。该项目的长期目标之一是开发基因诊断测试，以帮助识别患冠心病风险增加的人，与目前使用的传统风险因素（如低密度脂蛋白升高或血压升高）的方法大致相同。如果5-LO/LT途径被证明对CAD很重要，那么最有希望的好处之一可能是将目前用于哮喘的现有药物应用于CAD的管理，这可能会导致更新和更有效的治疗方法。