A headshot photo of Eric E Kelley.

Eric E Kelley, PhD

Associate Professor

Contact Information

Phone
304-293-3064

Affiliations

  • Department of Physiology & Pharmacology

Graduate Training

  • PhD, Free Radical Biology, University of Iowa

Fellowships

  • Postdoc, Center for Free Radical Biology, UAB

Research Interests

Eric E. Kelly, Ph.D., Associate Professor, Department of Physiology and Pharmacology
Graduate program affiliation: Cellular and Integrative Physiology
PhD: University of Iowa, Free Radical Biology
Postdoctoral Training: UAB, Center for Free Radical Biology
Office: 3074 Health Science Center North

Phone: 304-293-6064

eric.kelly@hsc.wvu.edu

RESEARCH INTEREST

  1. Redox- and NO-mediated signaling in vascular dysfunction and cancer.
  2. Interplay between ROS, NO and uric acid in metabolic and cardiovascular dysfunction allied to obesity.
  3. Manipulating oxidant and NO generation in cerebral vessels following ischemic stroke.
  4. Oxidant signaling in aging.
  5. Xanthine oxidase in hemolytic disease (e.g. sepsis, sickle cell, malaria, cardiac bypass etc.)

RESEARCH DESCRIPTION

The overarching theme of the Kelley lab orbits around the convergence of inflammation with enhanced rates of oxidant generation; both of which are hallmarks of metabolic syndrome and diabetes yet, are allied to a plethora of disease processes including cancer.  A current and specific focus of our efforts involves manipulating the enzymatic activity of xanthine oxidase (XO), a critical source of reactive species and uric acid in obesity/diabetes. Capitalizing on the recent discovery that XO can also catalyze the reduction of nitrate (NO3-) and nitrite (NO2-) to salutary NO, we have recently observed that elevation of circulating levels of NO2- /NO3- in obese mice results in beneficial outcomes including reduction in oxidative stress, blood glucose and improved cardiopulmonary function. With obesity/diabetes being epidemic in the U.S. there is a pressing need to intervene by addressing the root causes. This being said, there is an exploding population of obese/diabetic patients presently in need of treatment for related cardiovascular disease. By focusing on XO, our findings are rapidly translatable to the clinic via off-label application of FDA-approved XO inhibitors and/or sources of NO3- /NO2-.

A second recently-funded aim of our lab is to examine XO as a target for ischemic stroke in the context of obesity. By applying the lessons learned with our obesity/metabolic studies, we hope to produce a treatment approach that will augment the current clinical strategy and/or extend the narrow and limited treatment window provided by TPA.

Our third major aim is to identify critical redox-mediated contributors to aging. This project is a collaborative effort with the Scripps Institute where we are exploring the Free Radical Theory of Aging using a murine model of human progeria.  Our goal is to define the interplay between diminished antioxidant capacity, elevated mitochondrial ROS generation and enhanced activity of enzymatic sources of oxidants that are correlative with both normal and accelerated aging.

A fourth aim focuses on identifying XO as a drug target for hemolytic disease. Our recent findings demonstrate a robust elevation in plasma XO during hemolytic crisis. We are collaborating with partners at Pitt and LSU, Shreveport to develop a novel small molecule compound that inhibits XO from binding to the vascular endothelium and thus alleviate vascular dysfunction. 

While these current aims represent a wide range of techniques, our primary strength is redox biology and thus we actively collaborate with experts in various fields including cardiology and oncology to amplify our research prowess while ensuring success.

Recent Publications

Publications (past 5 years)

  1. He J, Hu B, Shi X, Weidert ER, Lu P, Xu M, Huang M, Kelley, EE, Xie W. Activation of the aryl hydrocarbon receptor sensitizes mice to non-alcoholic steatohepatitis by deactivating the mitochondrial sirtuin deacetylase Sirt3. Mol Cell Biol, 33(10):2047-55, 2013.
  2. Cantu-Medellin, N. and Kelley, E.E. Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: Insights regarding where, when and how. Nitric Oxide, 34:19-26, 2013.
  3. Cantu-Medellin, N. and Kelley, E.E. Xanthine oxidoreductase-catalyzed reactive species generation: A process in critical need of reevaluation. Redox Biol, 1(1):353-358, 2013.
  4. Ranayhossaini, D.J., Rodriguez, A.R., Chen, B., Mallampali, R., Kelley, E.E., Csanyi, G., Sahoo, S., Gladwin, MT, Romero, G.G., and Pagano, P.J. J Biol Chem, 288(51):36437-50, 2013.
  5. Kelley, E.E., Baust, J., Gor, S., Cantu-Medellin, N., Devlin, J.E., St. Croix, C.M., Champion, H.C., Freeman, B.A., and Khoo, N.K.H. Inhibition of Obesity-induced Pulmonary Arterial Hypertension by Fatty Acid Nitroalkene Derivatives. Cardiovasc Res, 101(3):352-63, 2014. PMID: 24385344.
  6. Weidert E.R., Schoenborn, S.O., Cantu-Medellin, N., Coughoule, K.V., Jones, J.P. and Kelley, E.E. Inhibition of xanthine oxidase by the aldehyde oxidase inhibitor raloxifene: Implications for identifying molybdopterin nitrite reductases. Nitric Oxide, 37C:41-45, 2014. PMID: 24406683.
  7. King, A.L., Polhemus, D.J., Bhushan, S., Otsuka, H., Kondo, K., Nicholson, C., Bradley, J.M., Islam, K.N., Calvert, J.W., Y., Dugas, T.R., Kelley, E.E., Elrod, J.W., Wang, R., and Lefer, D.J. Endothelial Nitric Oxide Synthase (eNOS) Regulation by Cystathione Gamma Lyase (CSE): Crosstalk Between Hydrogen Sulfide (H2S) and Nitric Oxide (NO) Signaling Pathways. Proc Natl Acad Sci USA, 111(8):3182-7, 2014. PMID: 24516168.
  8. Honavar, J., Bradley, E., Bradley, K., Oh, J.Y., Kelley E.E., Cantu-Medellin, N., Doran S., D’ellitalia L., Matalon, S. and Patel, R.P. Chlorine gas exposure disrupts nitric oxide homeostasis in the pulmonary vasculature. Toxicology, 321:96-102, 2014. PMID: 24769334.
  9. Kelley, E.E., Comment on Fabbrini et al. Effect of plasma uric Acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes, 63(9):e18. 2014. PMID: 25146479.
  10. Wang, J., Krizowski, S., Fischer, K., Tejero, J., Zhao, X., Wang, L., Frizzell, S., Kelley, E.E., Shiva, S., Zhang, Y., Hille, R., Basu, P., Schwarz, G. and Gladwin, M.T. Sulfite oxidase catalyzes single electron transfer at molybdenum domain to reduce nitrite to nitric oxide. Antioxid Redox Signal, 23(4):283-94, 2014. PMID: 25314640.
  11. Wu, F., Szczepaniak, W.S., Shiva, S., Liu, H., Wang, Y., Wang, L., Kelley, E.E., Chen, A.F., Pagano, P.J., Gladwin, M.T. and McVerry, B.J.  Endothelial NOS uncoupling by Nox2-dependent oxidative modification contributes to endothelial barrier dysfunction in inflammatory acute lung injury. Am J Physiol Lung Cell Mol Physiol, 307(12):L987-97, 2014. PMID: 25326583.
  12. Bahnson E.S.M., Koo, N., Cantu-Medellin, N., Tsui, A.Y., Havelka, G.E., Vercammen, J.M., Jiang, Q., Kelley, E.E. and Kibbe, M.R. Nitric Oxide Inhibits Neointimal Hyperplasia following Vascular Injury via Differential, Cell-specific Modulation of SOD-1 in the Arterial Wall. Nitric Oxide, 44:8-17, 2014. PMID: 25460325.
  13. Morales, R.C., Bahnson, E.S., Havelka, G.E., Cantu-Medellin, N., Kelley, E.E., Kibbe, M.R. Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide. Redox Biol. 4:226-233, 2015. PMID: 25617803.
  14. Madigan, M.C., Mceananey, R.M., Shukla, A.J., Hong, G., Kelley, E.E., Tarpey, M.M., Gladwin, M.T., Zuckerbraun, B.S. and Tzeng, E. Xanthine oxidase function contributes to normal wound healing. Mol Med, 21(1):313-22, 2015. PMID: 25879627.
  15. Kelley, E.E. Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase. Arch Toxicol, 89(8):1193-207, 2015. PMID: 25995007.
  16. Kelley, E.E. A new paradigm for XOR-catalyzed reactive species generation in the endothelium. Pharmacol Rep. 67(4):669-74, 2015. PMID: 26321266.
  17. Khoo, N.K., Cantu-Medellin, N., St Croix, C.M. and Kelley, E.E. In vivo immuno-spin trapping: Imaging the footprints of oxidative stress. Curr Protoc Cytom. 74:12.42.1-12, 2015. PMID: 26423693.
  18. Koenitzer, J.R., Bonacci, G., Woodcock, S.R., Chen-Shan, C., Cantu-Medellin, N., Kelley, E.E. and Schopfer, F.J. Fatty acid nitroalkenes induce resistance to ischemic cardiac injury by modulating mitochondrial respiration at complex I. Redox Biol. .17;8:1-10, 2015. PMID: 26722838.
  19. Trostchansky, A., Quijano, C., Yadav, H., Kelley, E.E. and Cassina, A. Interplay Between Oxidative Stress and Metabolism in Signalling and Disease. Ox. Med. Cell. Longev. Epub ahead of print: 3274296. Jan 2016. PMID: 26949446.
  20. Kotlarczyk, M.P., Billaud, M., Green, B.R., Hill, J.C., Shiva, S., Kelley, E.E., Phillippi, J.A., Gleason, T.G. Ann Thorac Surg.  102(4):1274-81, 2016. PMID: 27283108.
  21. Ghoshal, P., Singla, B., Lin, H.P., Feck, D.M., Cantu-Medellin, N., Kelley, E.E., Haigh, S., Fulton, D. and Csanyi, G. Nox2-mediated PI3K and Cofilin Activation Confers Alternate Redox Control of Macrophage Pinocytosis. Antioxid Redox Signal, 26(16):902-916, 2017. PMID: 27488058.
  22. Dezfulian, C., Kenny, E., Lamade, A., Misse, A., Krehel, N., St Croix, C., Kelley E.E., Jackson, T.C., Uray, T., Rackley, J., Kochanek, P.M., Clark, R.S and Bayir, H. Mechanistic characterization of nitrite-mediated neuroprotection after experimental cardiac arrest. J Neurochem. 139(3):419-431, 2016. PMID: 27507435.
  23. Csanyi, G., Feck, D.M., Ghoshal, P., Singla, B., Lin, H.P., Nagarajan, S., Meijles, D.N., Al Ghouleh, I., Cantu-Medellin, N.C., Kelley, E.E., Mateuszuk, L.M., Isenberg, J.S., Watkins, S.C. and Pagano P.J. CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. Antioxid Redox Signal., 26(16):886-901, 2017. PMID: 27958762.
  24. Billaud M, Phillippi JA, Kotlarczyk MP, Hill JC, Ellis BW, St Croix CM, Cantu-Medéllin N, Kelley E.E., Gleason TG. Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve. J Thorac Cardiovasc Surg., 17:31118-22017, 2017.  PMID: 28651938.
  25. Rahaman MM, Nguyen AT, Miller MP, Hahn SA, Sparacino-Watkins C, Jobbagy S, Carew NT, Cantu-Medellin N, Wood KC, Baty CJ, Schopfer FJ, Kelley E.E., Gladwin MT, Martin E, Straub AC. Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling. Circ Res., 121(2):137-148, 2017. PMID: 28584062.
  26. Kelley E.E., Paes AM, Yadav H, Quijano C, Cassina A, Trostchansky A. Interplay between Oxidative Stress and Metabolism in Signalling and Disease. Oxid Med Cell Longev. 2017 PMID: 28203320.
  27. Branyan K.W., DeVallance, E.R., Lemaster, K.A., Skinner, R.C., Bryner, R., Olfert, I.M., Kelley, E.E., Frisbee, J.C., Chantler, P.D. Role of Chronic Stress and Exercise on Microvascular Function in Metabolic Syndrome. Med Sci Sports Exerc. 2017 Dec 21. [Epub ahead of print] PMID: 29271845.
  28. Robinson, A.R., Yousefzadeh, M.J., Rozgaja, T.A., Wang, J., Li, X., Tilstra, J.S., Feldman, C.H., Gregg, S.Q., Johnson, C.H., Skoda, E.M., Frantz, M.C., Bell-Temin, H., Pope-Varsalona, H., Gurkar, A.U., Nasto, L.A., Robinson, R.A.S., Fuhrmann-Stroissnigg, H., Czerwinska, J., McGowan, S.J., Cantu-Medellin, N., Harris, J.B., Maniar, S., Ross, M.A., Trussoni, C.E., LaRusso, N.F., Cifuentes-Pagano, E., Pagano, P.J., Tudek, B., Vo, N.V., Rigatti, L.H., Opresko, P.L., Stolz, D.B., Watkins, S.C., Burd, C.E., St. Croix, C.M., Siuzdak, G., Yates, N.A., Robbins, P.D., Wang, Y., Wipf, P., Niedernhofer, L.J. and Kelley E.E. Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol. 17:259-273, 2018. PMID: 29747066.
  29. Mandler, W.K., Nurkiewicz, T.R., Porter, D.W., Kelley, E.E. and Olfert, M.I. Microvascular dysfunction following multi-walled carbon nanotube exposure is mediated by thrombospondin-1 receptor CD47. In Press, Tox. Sci. (May 9, 2018) TOXSCI-18-0055.R1.
  30. Bilan, V., Schneider, F., Novelli, E.M., Kelley, E.E., Sriva, S., Gladwin, M.T., Jackson, E.K. and Tofovic, S.P. Experimental Intravascular Hemolysis Induces Hemodynamic and Pathological Pulmonary Hypertension-Association with Accelerated Purine Metabolism. Pulm Circ. [Epub ahead of print], 2018, doi: 10.1177/2045894018791557. PMID: 30003836.
  31. Gurkar, A.U., Robinson, A.R., Cui, Y., Li, X., Allani, S.K., Webster, A., Muravia, M., Fallahi, M., Weissbach, H., Robbins, P.D., Wang, Y., Kelley, E.E., St. Croix C.M., Niedernhofer, L.J. and Gill, M.S. Redox Biol. [Epub ahead of print] 2018, doi: 10.1016/j.redox.2018.06.005. PMID: 30031267.
  32. Harmon, D., Wu, C., Dedousis, N., Sipula, I., Stafanovic-Racic, M., Schoiswohl, G. O'Donnell, C., Alonso, L., Kershaw, E., Kelley, E.E., and O'Doherty, R.M. Adipose Tissue Derived Free Fatty Acids Initiate Myeloid Cell Accumulation in Mouse Liver in States of Lipid Oversupply. AJP-Endocrinology and Metabolism, E-00172-2018 in press, Aug 1, 2018.

Book Chapters

  1. Kelley, E.E. Chapter: The Biochemistry of molybdopterin protein-catalyzed nitrate/nitrite reductase activity. In: Nitric Oxide, Edited by Lou Ignarro, 3rd Edition in press, 2018.