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.
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