I am an assistant 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 and UNC Institute for Pharmacogenomics and Individualized Therapy.

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 disease in order to develop novel therapeutic strategies that will reduce the burden of this major public health problem. 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 current focus of my research program is twofold. First, we seek to characterize the contribution of cytochrome P450-mediated eicosanoid metabolism to the regulation of 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 disease in targeted subsets of the population. Second, we aim to define the mechanisms underlying the adverse cardiovascular effects of drugs currently utilized in patients.

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. Consequently, inhibitors of soluble epoxide hydrolase (sEH) and 20-HETE biosynthesis are under development for the treatment 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. Using a translational approach, the primary focus of my research program has been 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, Regulation of Vascular Responsiveness to Bradykinin, sponsored by NHLBI/NIH (Principal Investigator, Nancy J. Brown, Vanderbilt University).
• Lee CR, Principal Investigator, Functional Characterization of an Interaction between the ‑765G>C Polymorphism in Cyclooxygenase-2 and Aspirin Use in Humans, sponsored by UNC University Research Council.
• Schuck RN, Pre-Doctoral Fellow, Translational Characterization of Arachidonic Acid Metabolism in Vascular Inflammation and Cardiovascular Disease (AHA 11PRE7240059), sponsored by the American Heart Association (Sponsor, Craig R. Lee).