July 17, 2007
Craig Lee, PhD, an assistant professor at the UNC School of Pharmacy, has received a $132,000 beginning grant-in-aid from the American Heart Association.
Lee will use the two-year grant, titled “P450 Epoxygenase Pathway and Atherosclerotic Cardiovascular Disease”, to study the relationship between genetic variation in the cytochrome P450 epoxygenase pathway and mechanisms underlying the risk of cardiovascular disease.
Cytochromes P450 are a metabolic enzyme family present throughout the body. The pathway Lee is studying is active in the cardiovascular system and forms epoxyeicosatrienoic acids (also known as EETs), which dilate blood vessels and have anti-inflammatory effects. About ten to twenty-five percent of the population, however, has genetic variants that result in a dysfunctional pathway.
“Some of our previous work at the population level in humans has demonstrated that people with genetic variants which make this pathway dysfunctional are at higher risk of having a heart attack or stroke,” says Lee, who joined the School’s Division of Pharmacotherapy and Experimental Therapeutics in 2006. “However, no one has really addressed how and why that happens. We are interested in learning more about the pathway and learning more about its relevance in treating cardiovascular disease.”
Lee will conduct a laboratory study to determine if mice expressing more P450s in their endothelial cells are better protected against atherosclerosis, a condition in which fatty materials collect along the artery walls, causing the blood vessels to harden and even become blocked. In addition, he will conduct a clinical study of human patients with atherosclerosis to measure a variety of factors that predict the risk of heart attack or stroke, including the ability of blood vessels to dilate, known as endothelial function.
The goal is to determine whether the genetic variants causing the dysfunctional pathway result in worse endothelial function in patients with cardiovascular disease, which may help explain why they have a higher risk of heart attacks or strokes.
“We hope this would enable us to learn more about the relevance of the pathway in human patients with cardiovascular disease,” Lee says. “In addition to that, we think this may help identify subsets of the population that may be most likely to respond to some new therapies that are in development. If you are genetically susceptible to a dysfunctional pathway, you may be more likely to respond to a therapy that targets the pathway.”
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