Craig Lee, Pharm.D., Ph.D.

Associate Professor

Craig Lee, Pharm.D, Ph.D. is an associate professor in the UNC Eshelman School of Pharmacy’s Division of Pharmacotherapy and Experimental Therapeutics. Lee is a licensed pharmacist in North Carolina, and is trained as a clinical/translational pharmaceutical scientist with expertise in cytochrome P450 metabolism, cardiovascular experimental therapeutics, and precision medicine/pharmacogenomics.

Since initiation of his faculty appointment in 2006, Lee has established a highly collaborative and translational research program that integrates mechanistically-driven rodent and cell-based preclinical models with observational and interventional clinical studies. He has received funding from the National Institutes of Health and American Heart Association, authored over 65 manuscripts and over 75 abstracts in the areas of cytochromes P450, eicosanoid and drug metabolism, pharmacogenomics, and experimental therapeutics, and has served as the major research advisor for three Pharm.D./Ph.D. graduate students, 11 post-doctoral fellows, 14 professional/undergraduate students.

Lee currently serves as director of the School’s Research and Scholarship in Pharmacy pathway for Pharm.D. students, and is actively engaged as a teacher and mentor in the School’s professional, graduate and fellowship programs.

He is also a member of the inter-disciplinary UNC Center for Pharmacogenomics and Individualized Therapy, UNC McAllister Heart Institute and UNC Nutrition Obesity Research Center.

Pharm.D.
2000
University of North Carolina, Chapel Hill, NC

Fellowship, Clinical Research / Drug Development
2002
University of North Carolina, Chapel Hill, NC/
GlaxoSmithKline, Research Triangle Park, NC

Ph.D. in Pharmaceutical Sciences
2006
University of North Carolina, Chapel Hill, NC

The overall objective of Craig Lee’s research program is to improve understanding of the key mechanisms underlying inter-individual variability in drug response as a means to develop novel therapeutic strategies that will improve public health.

The major scientific focus of Lee’s research is the metabolism of drugs and eicosanoids by the cytochromes P450 enzyme system. The major therapeutic area of application of his research is cardiovascular and metabolic disease.

His laboratory seeks to identify and elucidate the key factors that exacerbate inter-individual variability in the metabolism of and response to drugs currently on the market, and determine whether implementation of genomic and biomarker-guided drug selection and dosing strategies can reduce this variability in metabolism and response and improve patient outcomes.

His laboratory also seeks to develop a thorough understanding of how cytochrome P450-derived eicosanoids (bioactive lipid mediators of arachidonic acid) regulate hepatic and extra-hepatic inflammatory responses, and determine whether modulation of this pathway will serve as an effective anti-inflammatory and end-organ protective therapeutic strategy for cardiovascular and metabolic disease.

Lee’s contributions to science are described below.

The focus of Lee’s clinical pharmacology training and early research experiences centered on identifying and elucidating key factors that underlie inter-individual variability in cytochrome P450 (CYP)-mediated drug metabolism. His contributions to the field have primarily occurred in the area of pharmacogenomics with a focus on genetic variation in the CYP2C subfamily. Notable publications include:

  • Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in vitro and human data. Pharmacogenetics. 2002; 12(4):251-63. [PMID: 11927841]
  • Lee CR, Pieper JA, Hinderliter AL, Blaisdell JA, Goldstein JA. Evaluation of CYP2C9 metabolic activity with tolbutamide in CYP2C9*1 Clin Pharmacol Ther. 2002; 72(5):562-71. [PMID: 12426520]
  • Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA. Tolbutamide, flurbiprofen and losartan as probes of CYP2C9 activity in humans. J Clin Pharmacol. 2003;43(1):84-91. [PMID: 12520632]

A major focus of Lee’s research program over the past decade has been to understand how cytochrome P450 (CYP)-mediated metabolism of endogenous fatty acids (notably arachidonic acid) into bioactive lipids influences hepatic and extra-hepatic inflammatory responses with the expectation that these effects can be modulated in clinically relevant pathological conditions. Lee’s laboratory has demonstrated that activation of the innate immune response downregulates hepatic and extrahepatic CYP-mediated eicosanoid biosynthesis, and that therapeutic restoration of CYP-derived epoxyeicosanoids (EETs) elicits potent anti-inflammatory and protective effects in preclinical models of cardiovascular and metabolic disease. Notable publications include:

  • Theken KN, Deng Y, Kannon MA, Miller TM, Poloyac SM, Lee CR. Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism. Drug Metab Dispos. 2011; 39(1):22-29. [PMID: 20947618]
  • Deng Y, Edin ML, Theken KN, Schuck RN, Flake GP, Kannon MA, DeGraff LM, Lih FB, Foley J, Bradbury JA, Graves JP, Tomer KB, Falck JR, Zeldin DC, Lee CR. Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J. 2011; 25(2):703-713. [PMID: 21059750]
  • Zha W, Edin ML, Vendrov KC, Schuck RN, Lih FB, Jat JL, Bradbury JA, DeGraff LM, Hua K, Tomer KB, Falck JR, Zeldin DC, Lee CR. Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity. J Lipid Res. 2014; 55:2124-36. [PMID: 25114171]
  • Schuck RN, Zha W, Edin ML, Gruzdev A, Vendrov KC, Miller TM, Xu Z, Lih FB, DeGraff LM, Tomer KB, Jones HM, Makowski L, Huang L, Poloyac SM, Zeldin DC, Lee CR. The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease. PLoS One. 2014; 9(10):e110162. [PMID: 25310404]
  • Wells MA, Vendrov KC, Edin ML, Ferslew BC, Zha W, Nguyen BKH, Church RJ, Lih FB, DeGraff LM, Brouwer KLR, Barritt AS, Zeldin DC, #Lee CR. Characterization of the cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis. Prostaglandins Other Lipid Mediat. 2016; 125:19-29. [PMID: 27401401]

Lee has made significant contributions to an inter-institutional collaborative effort that has generated and characterized transgenic mice with endothelial overexpression of the primary human CYP epoxygenases (CYP2J2, CYP2C8). These mouse models have significantly advanced the field by elucidating the functional role of endothelial-derived epoxyeicosanoids in multiple pathophysiologic conditions including hypertension, ischemia reperfusion injury, tumor development and metastasis, wound healing and organ regeneration, and metabolic disease. Notable publications include: (*denotes equal contribution)

  • *Lee CR, *Imig JD, Edin ML, Foley J, DeGraff LM, Bradbury JA, Graves JP, Lih FB, Clark J, Myers P, Perrow AL, Lepp AN, Kannon MA, Ronnekleiv OK, Alkayed NJ, Falck JR, Tomer KB, Zeldin DC. Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. FASEB J. 2010; 24(10):3770-81. [PMID: 20495177]
  • *Panigrahy D, *Edin ML, *Lee CR, *Huang S, Bielenberg DR, Butterfield CE, Barnés CM, Mammoto A, Mammoto T, Luria A, Benny O, Chaponis DM, Dudley AC, Greene ER, Vergilio J, Pietramaggiori G, Scherer-Pietramaggiori SS, Short SM, Seth M, Lih FB, Tomer KB, Yang J, Schwendener RA, Hammock BD, Falck JR, Manthati VM, Ingber DE, Kaipainen A, D’Amore PA, Kieran MW, Zeldin DC. Epoxy-eicosanoids stimulate multi-organ metastasis and tumor dormancy escape in mice. J Clin Invest. 2012; 122(1):178-91. [PMID: 22182838]
  • Panigrahy D, Kalish BT, Huang S, Bielenberg DR, Le HD, Yang J, Edin ML, Lee CR, Benny O, Mudge DR, Butterfield CE, Mammoto A, Mammoto T, Inceoglu B, Jenkins RL, Simpson M, Akino T, Lih FB, Tomer KB, Ingber DE, Hammock BD, Falck JR, Manthati VL, Kaipainen A, D’Amore PA, Puder M, Zeldin DC, Kieran MW. Epoxy-eicosanoids promote organ and tissue regeneration. Proc Natl Acad Sci U S A. 2013; 110(33):13528-33. [PMID: 23898174]
  • Cheng J, Edin ML, Hoopes SL, Li H, Bradbury JA, Graves JP, DeGraff LM, Lih FB, Garcia V, Shaik JS, Tomer KB, Flake GP, Falck JR, Lee CR, Poloyac SM, Schwartzman ML, Zeldin DC. Vascular characterization of mice with endothelial expression of cytochrome P450 4F2. FASEB J. 2014; 28(7):2915-31. [PMID: 24668751]
  • Abraham NG, Sodhi K, Silvis AM, Vanella L, Favero G, Rezzani R, Lee CR, Zeldin DC, Schwartzman ML. CYP2J2 targeting to endothelial cells attenuates adiposity and vascular dysfunction in mice fed a high-fat diet by reprogramming adipocyte phenotype. Hypertension. 2014;64:1352-61. [PMID: 25245389]

Lee’s research program has utilized genomics and biomarkers to translate mechanistically-focused preclinical discoveries into humans, and determine which subsets of the population may be most likely to respond to the therapeutic strategies under evaluation in his laboratory. Most notably, using functionally relevant germline genetic variants and eicosanoid metabolite biomarkers, Lee has identified subsets of the population predisposed to low EET levels and elevated cardiovascular disease risk. Through collaborative sharing of biological samples and cardiovascular phenotyping data, Lee has also contributed to the translation of biomarker discoveries in the laboratories of his collaborators. Notable publications include:

  • Lee CR, North KE, Bray MS, Fornage M, Seubert JM, Newman JW, Hammock BD, Couper DJ, Heiss G, Zeldin DC. Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Hum Mol Genet. 2006; 15(10):1640-49. [PMID: 16595607]
  • Lee CR, Pretorius M, Schuck RN, Burch LH, Bartlett J, Williams SM, Zeldin DC, Brown NJ. Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans. Hypertension. 2011;57(1):116-22. [PMID: 21098312]
  • Lee CR, Bass A, Ellis K, Tran B, Steele S, Caughey M, Stouffer GA, Hinderliter AL. Relation between digital peripheral arterial tonometry and brachial artery ultrasound measures of vascular function in patients with coronary artery disease and in healthy volunteers. Am J Cardiol. 2012;109(5):651-57. [PMID: 22154090]
  • Schuck RN, Theken KN, Edin ML, Caughey M, Bass A, Ellis K, Tran B, Steele S, Simmons BP, Lih FB, Tomer KB, Wu MC, Hinderliter AL, Stouffer GA, Zeldin DC, Lee CR. Cytochrome P450-derived eicosanoids and vascular dysfunction in coronary artery disease patients. Atherosclerosis. 2013; 227(2):442-8. [PMID: 23466098]
  • Oni-Orisan A, Edin ML, Lee JA, Wells MA, Christensen ES, Vendrov KC, Lih FB, Tomer KB, Bai X, Taylor, JM, Stouffer GA, Zeldin DC, Lee CR. Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study. J Lipid Res. 2016; 57(1):109-19. [PMID: 26555503]
  • Bai X, Mangum KD, Dee RA, Stouffer GA, Lee CR, Oni-Orisan A, Patterson WC, Schisler JC, Viera AJ, Taylor JM, Mack CP. Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding. J Clin Invest. 2017; 127(2):670-80. [PMID: 28112683]

Lee’s research program has worked to determine whether clinical implementation of genomic and biomarker-guided drug selection and dosing strategies can reduce variability in drug metabolism and response and improve patient outcomes. Lee’s contributions to the field of precision medicine have primarily occurred in the area of pharmacogenomics with a scientific focus on genetic variation in drug metabolism and a clinical application focus in cardiovascular disease. This area has been a major focus of his research program in recent years, which has included leading UNC’s contribution the NIH Implementing GeNomics In PracTicE (IGNITE) Network. Notable publications include:

  • Lee JA, Lee CR, Reed BN, Plitt DC, Polasek MJ, Howell LA, Cicci JD, Tasca KE, Weck KE, Rossi JS, Stouffer GA. Implementation and evaluation of a CYP2C19 genotype-guided antiplatelet therapy algorithm in high-risk coronary artery disease patients. Pharmacogenomics. 2015; 16(4):303-313. [PMID: 25823779]
  • Cavallari LH, Beitelshees AL, Blake KV, Dressler LG, Duarte JD, Elsey A, Eichmeyer JN, Empey PE, Franciosi JP, Hicks JK, Holmes AM, Jeng L, Lee CR, Lima JJ, Limdi NA, Modlin J, Obeng AO, Petry N, Pratt VM, Skaar TC, Tuteja S, Voora D, Wagner M, Weitzel KW, Wilke RA, Peterson JF, Johnson JA. The IGNITE Pharmacogenetics Working Group: an opportunity for building evidence with pharmacogenetic implementation in a real-world setting. Clin Transl Sci. 2017; 10(3):143-6. [PMID: 28294551]
  • Borse MB, Dong OM, Polasek MJ, Farley JF, Stouffer GA, Lee CR. CYP2C19-guided antiplatelet therapy: a cost-effectiveness analysis of 30-day and 1-year outcomes following percutaneous coronary intervention. Pharmacogenomics. 2017; 18(12):1155-66. [PMID: 28745582]
  • Gonzalez D, Rao GG, Bailey SC, Brouwer KLR, Cao Y, Crona DJ, Kashuba ADM, Lee CR, Morbitzer K, Patterson JH, Wiltshire T, Easter J, Savage SW, Powell JR. Precision dosing: public health need, proposed framework, and anticipated impact. Clin Transl Sci. 2017; (in press). [PMID: in process]
  • Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, Kimmel SE, McDonough CW, Gong Y, Dave CV, Pratt VM, Alestock TD, Anderson RD, Alsip J, Ardati AK, Brott BC, Brown L, Chumnumwat S, Clare-Salzler MJ, Coons JC, Denny JC, Dillon C, Elsey AR, Hamadeh I, Harada S, Hillegass WB, Hines L, Horenstein RB, Howell LA, Jeng LJB, Kelemen MD, Lee YM, Magvanjav O, Montasser M, Nelson DR, Nutescu EA, Nwaba DC, Pakyz RE, Palmer K, Peterson JF, Pollin TI, Quinn AH, Robinson SW, Schub J, Skaar TC, Smith DM, Sriramoju VB, Starostik P, Stys TP, Stevenson JM, Varunok N, Vesely MR, Wake D, Weck KE, Weitzel KW, Wilke RA, Willig J, Zhao RY, Kreutz RP, Stouffer GA, Empey PE, Limdi NA, Shuldiner AR, Winterstein AG, Johnson JA on behalf of the IGNITE Network Pharmacogenetics Working Group. Multi-site investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv. 2017; (in press). [PMID: in process]

Positions and Employment
2000-present        Registered Pharmacist, North Carolina, Licensure #15450
2000-2002             Clinical Research/Drug Development Fellow, UNC School of Pharmacy / GlaxoSmithKline
2002-2006             Guest Researcher, Division of Intramural Research, NIH/NIEHS
2006-2012             Assistant Professor of Pharmacy, DPET, UNC Eshelman School of Pharmacy
2012-present        Associate Professor of Pharmacy (with Tenure), UNC Eshelman School of Pharmacy

Education and Training Programs
2008-2016             Division Director of Graduate Admissions, DPET, UNC Eshelman School of Pharmacy
2012-2016             Curricular Transformation Steering Committee, UNC Eshelman School of Pharmacy
2016-2017             Division Director of Graduate Studies, DPET, UNC Eshelman School of Pharmacy
2016-present        Director, Research and Scholarship in Pharmacy pathway, UNC Eshelman School of Pharmacy

Training Grants
2010-present        Faculty, Pre-Doctoral Training Program in Integrative Vascular Biology (T32 HL069768)
2011-present        Faculty, UNC-Duke Collaborative Clinical Pharmacology Postdoctoral Training Program (T32 GM086330)
2016-present        Faculty, Post-Doctoral Training Program in Genetic Epidemiology of Heart, Lung, and Blood Traits (GenHLB) (T32 HL129982)

Professional Memberships
2000-present        Full Member, American College of Clinical Pharmacy (ACCP)
2002-present        Full Member, American Society for Clinical Pharmacology and Therapeutics (ASCPT)
2003-present        Professional Member, American Heart Association (AHA)
2006-present        Member, American Society for Pharmacology and Experimental Therapeutics (ASPET)
2015-present        Affiliate Member, NIH Implementing GeNomics In PracTicE (IGNITE) Network

Professional Service
2009-2014             Scientific Member, Institutional Review Board, NIH/NIEHS
2010                      Study Section Member (ad hoc), Special Emphasis Panel, 2010/05 ZES1 LWJ-V (01) 2
2010-present        Editorial Board: Frontiers in Physiology, Prostaglandins and Other Lipid Mediators, Frontiers in Pharmacology
2012-present        Co-Chair, Poster Session, International Winter Eicosanoid Conference
2013                      Study Section Member (ad hoc), Special Emphasis Panel, 2013/08 ZRG1 BDCN-A (40)
2013-2017             Member, Clinical Pharmacology Committee, AHA Council on Clinical Cardiology
2014-present        Member, Membership & Communications Committee, AHA Council on Functional Genomics and Translational Biology
2017                      Study Section Member (ad hoc), Special Emphasis Panel, 2017/03 ZRG1 GGG D (90) 

Honors
2003-2006             Ruth L. Kirschstein Individual National Research Service Award (F32), NIH/NIEHS
2005-2006             Postdoctoral Award for Research Excellence, UNC-Chapel Hill
2005                      Elizabeth Barrett-Connor Research Award in Epidemiology for Young Investigators, AHA Council on Epidemiology and Prevention
2006, 2010            Travel Award, Winter Eicosanoid Conference
2011                      Junior Investigator Award, ACCP Cardiology Practice and Research Network
2011                      Fellow, American College of Clinical Pharmacy (FCCP)
2012                      Tenure, University of North Carolina at Chapel Hill
2015                      Fellow, American Heart Association, Council on Clinical Cardiology (FAHA)

AHA 16GRNT29300003 (Grant-in-Aid)                                              Lee, CR (PI)                7/1/16 – 6/30/18

American Heart Association, Mid-Atlantic Affiliate

Novel Biomarkers of Eicosanoid Metabolism in Coronary Artery Disease

The major goal of this project is to project is to elucidate the relationship between inter-individual variation in the cytochrome P450 epoxyeicosanoid (EET) metabolic pathway and prognosis in patients with coronary artery disease (CAD), and facilitate the development novel therapeutic strategies for CAD that target subsets of the population predisposed to low EET levels and poor prognosis.

Role: Principal Investigator

Tier 3 Pilot Grant                                                                                 Wiltshire, T (PI)           6/1/17 – 5/31/19

The Eshelman Institute for Innovation

Pharmacogenetic Implementation: The Actionable Genome

The major goal of this pilot project is to determine the feasibility of implementing a novel preemptive genotyping assay (PGx1) across five specialist areas of medicine in a major academic medical center. A key secondary goal is to assess the impact on medication prescribing and projected cost-effectiveness.

Role: Co-Investigator

Pending Research Support

R03 HD092370-01                                                                                 Boggess, KA (PI)

NIH/NICHD

Phase II Study of Nicotinamide (vitamin B3-amide) in Early-Onset Preeclampsia

The major goal of this phase II clinical trial is to evaluate the ability of nicotinamide, a nontoxic water-soluble amide of vitamin B3, to lower maternal blood pressure and reduce risk of development of severe hypertension in women with early-onset preeclampsia.

Role: Co-Investigator

Recently Completed Research Support

R01 GM088199-01-05                                                                           Lee, CR (PI)                8/1/09 – 5/31/15

NIH/NIGMS

Cytochrome P450 Derived Eicosanoids and Inflammation

The major goal of this project was to define the contribution of cytochrome P450 (CYP) derived eicosanoids to the regulation of hepatic and cardiovascular inflammatory responses in vivo, and facilitate the development of new anti-inflammatory strategies with potential therapeutic application to numerous disease states in humans.

Role: Principal Investigator

R01 GM088199-S1-03-05                                                                     Lee, CR (PI)                8/1/11 – 5/31/14

NIH/NIGMS

NIH Research Supplement to Promote Diversity in Health-Related Research

The major goal of this supplement to R01 GM088199 was to provide a graduate student support as he developed his dissertation research proposal and submitted an extramural fellowship application.

Role: Principal Investigator

 

TraCS # 550KR61307 (Pilot Grant)                                                    Boggess, KA (PI)        3/1/14 – 2/28/15

North Carolina Translational and Clinical Sciences (NC TraCS) Institute

A Dose Escalation Study of Nicotinamide Supplementation in Early Onset Preeclampsia

The major goal of this CTSA-funded pilot project was to evaluate the safety of oral nicotinamide administration in women with early onset preeclampsia in order to guide the design of a prospective clinical trial.

Role: Co-Investigator

Tier 1 Pilot Grant                                                                                 Lee, CR (PI)                10/1/15 – 3/31/17

The Eshelman Institute for Innovation

Solving the Mystery of Highly Variable Drug Disposition in Pregnant Women: Are Unique Hepatic Drug Metabolizing Enzymes Activated during Pregnancy?

The major goal of this pilot project is to determine whether unique hepatic drug metabolizing enzymes are activated in the presence of the dramatic sex hormone changes that occur throughout pregnancy.

Role: Principal Investigator

Trainee Awards

AHA 11PRE7240059 (Pre-Doctoral Fellowship)                               Schuck, RN (PI)         7/1/11 – 6/30/13

American Heart Association, Mid-Atlantic Affiliate

Translational Characterization of Arachidonic Acid Metabolism in Cardiovascular Disease

This project provided stipend support for Robert N. Schuck during completion of his dissertation research.

Role: Sponsor (Co-Sponsor: Cam Patterson)

AHA 13PRE16470017 (Pre-Doctoral Fellowship)                             Oni-Orisan, A (PI)       7/1/13 – 6/30/15

American Heart Association, Mid-Atlantic Affiliate

Soluble Epoxide Hydrolase and Cardioprotection: Translation from Mice to Humans

This project provided stipend support for Akinyemi Oni-Orisan during completion of his dissertation research.

Role: Sponsor (Co-Sponsor: Darryl Zeldin)

AFPE Gateway to Research Scholarship                                         Wells, MA (PI)             6/30/15 – 6/30/16

American Foundation for Pharmaceutical Education

Translational Evaluation of Cytochrome P450-Derived Eicosanoid Metabolites as a Biomarker in Non-Alcoholic Steatohepatitis (NASH) Patients

This project provided support for Michael A. Wells during completion of his Doctor of Pharmacy Honors research project, and facilitated his exploration of science as a future career direction.

Role: Major Advisor

Craig Lee News