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Gary Wright, Ph.D.
Key Laboratory Personnel:
Collette Hunt, B.S., Research Assistant
Minghua Chen, B.S., Research Technician
Andrew Miller, B.S., Research Technician
Joe Wu, M.S., Graduate Student
Victor Paramov, Ph.D., Research Assistant Professor
Education and Professional Background:
Dr. Wright is an associate professor of Pharmacology at the Quillen College of Medicine in Johnson City, Tennessee. He received his doctorate at the Marshall University, with post-doctoral training at NIEHS/NIH and at Kumamoto University. He is a fellow of the American Heart Association and a member of the editorial board for the Journal of Molecular and Cellular Cardiology.
Regulation of mitochondria by the PHD O2-sensor/HIF Axis.
Mechanisms of Mitochondrial dysfunction.
Dr Wrights research efforts can be categorized into two primary foci:
1. Exploring the role of the prolyl hydroxylase (PHD) oxygen-sensing pathway on cellular metabolism, (patho)physiology and mitochondrial function. Using several heart model systems that include isolated mitochondria, cardiomyocyte cultures and the langendorf heart preparation our studies have probed the physiological and metabolic changes that are directed by the PHD pathway. This recent work has established several novel responses and compensatory mechanisms that are induced by the PHD pathway. Continuing work will address the molecular mechanisms through which the PHD-induced physiological changes are accomplished.
2. Exploring the underlying causes of mitochondrial dysfunction in chronic pathology and ageing. Of particular interest is the hypothesis that the mitochondrial protein import pathway (MPIP) is highly susceptible to oxidative stress, and that disruption of this critical mitochondrial pathway underlies the mitochondrial dysfunction that is hallmark of many ageing related pathologies and toxin exposures. In recent work we find evidence that oxidative stress disrupts the newly identified disulfide relay system located within the mitochondrial intermembrane space. This leads to the selective depletion of critical components of the protein import machinery from the mitochondria. Future work will focus upon establishing a link between MPIP disruption and the mitochondrial dysfunction that is associated with a myriad of important diseases.
Active Research funding:
R01 HL084302-01 NIH/NHLBI (Wright, PI)
Role of the Prolyl Hydroxylase Oxygen-Sensor in Cardioprotection
Goals: To explore the protective mechanisms induced by the oxygen-sensing signal pathway in heart cells
He S, Rehman H, Wright GL, Zhong Z. Inhibition of inducible nitric oxide synthase prevents mitochondrial damage and improves survival of steatotic partial liver grafts. Transplantation. 2010 Feb 15;89(3):291-8.
Kasiganesan, H., Wright GL, Maria Assunta Chiacchio, Giuseppe Gumina Novel L-Adenosine Analogs as Cardioprotective Agents Bioorganic & Medicinal Chemistry, Bioorg Med Chem. 2009 Jul 15;17(14):5347-52.
Zhong Z, Ramshesh VK, Rehman H, Currin RT, Sridharan V, Theruvath TP, Kim I, Wright GL, Lemasters JJ. Activation of the Oxygen-Sensing Signal Cascade Prevents Mitochondrial Injury after Mouse Liver Ischemia-Reperfusion. Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G823-3..
Rehman, H., Connor, H.D., Ramshesh, V.K., Theruvath, T.P., Mason, R.P., Wright, GL, Lemasters, J.J., and Zhong Z. Ischemic preconditioning prevents free radical production and mitochondrial depolarization in small-for-size rat liver grafts. Transplantation 85(9) 1322-1331, 2008.
Sridharan, V., Guichard, J., Chuan-Yuan Li, Robin Muise-Helmricks, Craig Cano Beeson and Wright GL The oxygen-sensing signal cascade: metabolic rearrangements that include active suppression of O2 respiration, reduced ATP consumption and fumarate respiration. Am J Physiol (Cell Physiol.) 2008 Jul;295(1):C29-37.
Wright GL, Juanita Eldridge, Lina M. Obeid and Robin C. Muise-Helmericks. Akt3 Controls Mitochondrial Biogenesis in Primary Endothelial Cells. FASEB J. 2008 Sep;22(9):3264-75.
Sridharan V., Rachel M. Bailey, Harinath Kasiganesan, Craig Beeson and Wright, GL The prolyl hydroxylase oxygen-sensing pathway is cytoprotective and allows maintenance of mitochondrial membrane potential during metabolic inhibition. American Journal Physiology-(Cell Physiology) 2007 Feb;292(2):C719-28.
Kasiganesan, H., V. Sridharan and Wright GL Prolyl hydroxylase inhibitor treatment confers whole-animal hypoxia tolerance Acta Physiol (Oxf). 2007 Jun;190(2):163-9.
Wright G, Hanlon P, Amin K, Steenbergen C, Murphy E, Arcasoy MO. Erythropoietin receptor expression in cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury of adult rat hearts. FASEB J. 2004 Jun;18(9):1031-3
Wright G, Steenbergen C, Murphy E. Activation of the prolyl hydroxylase oxygen-sensor results in induction of GLUT1, HO-1, NOS-2 proteins, and confers protection from metabolic inhibition to cardiomyocytes. J. Biol. Chem. 2003 May 30;278(22):20235-9