Current Research Projects
I am an associate professor in the UNC Eshelman School of Pharmacy’s Division of Pharmacotherapy and Experimental Therapeutics (DPET). The mission of DPET is to optimize drug therapy through the generation, integration and translation of scientific information between the bench and the bedside, the patient and the population. I am also a member of the UNC McAllister Heart Institute, UNC Center for Pharmacogenomics and Individualized Therapy and UNC Nutrition Obesity Research Center.
The overall objective of my research program is to characterize the key mechanisms underlying inter-individual variability in the development, progression and treatment of cardiovascular and metabolic disease in order to develop novel therapeutic strategies that will reduce the burden of these major public health problems. Using genomic and biomarker-guided strategies, we seek to translate our laboratory discoveries into humans and determine which subsets of the population may be most likely to respond to the therapeutic strategies under evaluation in my laboratory.
The primary focus of my research program is twofold. First, we seek to characterize the contribution of cytochrome P450-mediated eicosanoid metabolism to the regulation of hepatic and cardiovascular inflammation in preclinical models and humans, and determine whether modulation of this metabolic pathway will serve as an effective anti-inflammatory therapeutic strategy for cardiovascular and metabolic disease in targeted subsets of the population. Second, we aim to define the mechanisms underlying inter-individual variation in the response to drugs currently utilized in patients with cardiovascular disease.
Cytochrome P450-Derived Eicosanoids and Cardiovascular Disease
The major focus of my research program is the metabolism of endogenous fatty acids by cytochromes P450 (CYPs). In parallel to the well-described cyclooxygenase and lipoxygenase pathways, enzymes from the CYP system also synthesize biologically active eicosanoids in the cardiovascular system and constitute the “3rd pathway” of arachidonic acid metabolism. Over the past 15-20 years it has become well-established that CYP-derived epoxyeicosatrienoic acids (EETs, vasodilation) and 20-hydroxyeicosatetraenoic acid (20-HETE, vasoconstriction) regulate vascular tone, and increasing EETs and suppressing 20-HETE each lower blood pressure in preclinical models of hypertension. More recently, it has become increasingly recognized that CYP-derived EETs and 20-HETE regulate numerous biological processes integral to the development and progression of CVD, such as inflammation, ischemia/reperfusion injury, angiogenesis, myocardial/vascular remodeling, and insulin resistance. Consequently, inhibitors of soluble epoxide hydrolase (sEH) and 20-HETE biosynthesis are in development. Using a translational approach, we seek to obtain a deeper mechanistic understanding of these biological effects, in both in vivo preclinical models and humans, in order to identify clinical applications for and subsets of the population most likely to derive benefit from therapeutic strategies that modulate CYP-mediated eicosanoid metabolism.
Ongoing Research Projects
- Lee CR, Principal Investigator, Cytochrome P450 Derived Eicosanoids and Inflammation (R01 GM088199), sponsored by NIGMS/NIH.
- Lee CR, Principal Investigator, Genomic and Metabolic Predictors of Endothelial Function in Patients with Atherosclerotic Cardiovascular Disease, sponsored by the North Carolina Translational and Clinical Sciences Institute and the American Heart Association.
- Lee CR, Co-Investigator, Evaluation of New Biomarkers of Acute Coronary Syndromes and Atherosclerotic Cardiovascular Disease in Patients Undergoing Coronary Angiography (Principal Investigator, George A. Stouffer, UNC Division of Cardiology).
- Lee CR, Co-Investigator, Retrospective Study of CYP2C19 Genotype and Anti-Platelet Therapy in a Cardiac Catheterization Lab Population (Principal Investigator, George A. Stouffer, UNC Division of Cardiology).
- Lee CR, Co-Investigator, The Role of the Functionally Relevant Single Nucleotide Polymorphisms CYP2J2 -50G>T (CYP2J2*7) and EPHX2 9846A>G (EPHX2 K55R) in Human Endothelial Function: the Environmental Polymorphism Registry, sponsored by NIEHS/NIH (Principal Investigator, Darryl C. Zeldin, NIEHS/NIH).
- Oni-Orisan A, Pre-Doctoral Fellow, Soluble Epoxide Hydrolase and Cardioprotection: Translation from Mice to Humans (AHA 13PRE16470017), sponsored by the American Heart Association (Sponsor, Craig R. Lee).