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Zheng
Dong, Ph.D.
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Professor, Department of Cellular Biology and Anatomy Departmental Director of Graduate Studies |
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Education and Training:
1989 B.Sc.,
Microbiology, Fudan University, Shanghai, P.R. China
1994 Ph.D., Physiology, Shanghai Institute of Physiology, Chinese Academy of Sciences
1998 Postdoc University of Texas Health Science Center at San Antonio
Research Experience:
2007 Professor, Department of Cellular Biology and Anatomy, MCG
Honors and
Awards :
2000 Lyndon B.
Johnson Research Award
American Heart Association
2004 Career Development Award VISN 7, VA
2005 Distinguished Faculty Award (Basic Science) School of Medicine, MCG
2005 Distinguished Research Award School of Graduate Studies, MCG
Extramural Grant Support:
National Institutes of Health
Department of Veteran’s Affairs
American Heart Association
Research Interest:
Cell injury and
adaptation under hypoxic/ischemic stress:
Lack of oxygen, i.e. hypoxia, is a key determinant of several
important pathogenic processes. Solid tumors adapt to hypoxic
microenvironments by selecting for death resistance, which confers poor
prognosis. On the other hand, hypoxia leads to massive cell death in
ischemic diseases including stroke, myocardial infarction and acute
renal failure. The objective of our research is to understand why some
cells die during hypoxia whereas others can adapt to the stress and
survive. We have shown that, under hypoxia, cells are injured due to
ATP-depletion and death by
necrosis ensues. Necrotic death of the hypoxic cells can be prevented
by glycine, a small amino acid. However, glycine is unable to rescue
the cells permanently, and after re-oxygenation, these cells undergo
apoptosis. Apoptosis of reoxygenated cells is mediated by the
mitochondrial pathway involving the proapoptotic molecule Bax,
cytochrome c, and caspases. Our current studies aim at further
understanding of the apoptotic mechanisms responsible for hypoxic
injury, the molecular basis of glycine cyto-protection and the
regulation of cell injury related genes by hypoxia. These studies are
expected to gain insights into the cell injury and adaptation mechanisms
activated by hypoxia-reoxygenation, and provide a theoretical basis for
developing novel strategies to reduce tissue pathology caused by
hypoxia/ischemia.
Molecular signaling of cisplatin-induced nephrotoxicity
Cisplatin, a widely used chemotherapy drug, induces renal cell injury and nephrotoxicity, which limits its therapeutic efficacy. We have demonstrated a role of p53 in renal cell apoptosis during cisplatin
treatment. Our recent work
further shows that PUMA-a, a
unique BH3-only Bcl-2 protein,
is induced by p53 under the
experimental condition. Upon
induction, PUMA accumulates
in mitochondria and
antagonizes Bcl-XL, resulting
in Bax activation, cytochrome
c release and apoptosis.
Future studies aim at the
identification of the signaling
pathways and molecules that
regulate p53 and PUMA. Work in
this direction may provide insights into
the cellular and molecular basis of cisplatin nephrotoxicity, and identify renal protective strategies to enhance the efficacy of the cancer therapy drug.
Key Words:
Apoptosis; Mitochondria; Cell injury and death; Adaptation; Gene regulation; Hypoxia; Cisplatin; Chemotherapy; Chemoprotection; Acute renal failure
Techniques:
Molecular cloning; promoter analysis; Northern, Southern & Western blot; Immunoprecipitation, Immunocytochemistry; Immunofluorescence; Cell death (apoptosis/necrosis) detection.
Recent Representative Publications:
Wei Q, Alam M, Wang M, Yu F, Dong Z. Bid Activation in Kidney Cells Following ATP Depletion in vitro and Ischemia in vivo. American Journal of Physiology 286(4):F803-809, 2004.
Dong Z, Wang J. Hypoxia Selection of Death Resistance Cells: a role for Bcl-XL. Journal of Biological Chemistry 279(10): 9215-9221, 2004.
Wang J, Wei Q, Wang CY, Hill WD, Hess DC, Dong Z. Minocycline up-regulates Bcl-2 and protects against cell death in the mitochondria. Journal of Biological Chemistry 279:19948-19954, 2004.
Wei Q, Wang J, Wang M, Yu F, Dong Z. Inhibition of Apoptosis by Zn2+ in Renal Tubular Cells Following ATP-depletion. American Journal of Physiology 287: F492-500, 2004.
Jiang M, Yi X, Hsu S, Wang C, Dong Z . Role of p53 in cisplatin-induced tubular cell apoptosis: dependent on p53 transcriptional activity. American Journal of Physiology: 287: 1140-1147, 2004.
Brooks C, Ketsawatsomkron P, Sui Y, Wang C, Yu F, Dong Z. Acidic pH Inhibits ATP depletion-induced Tubular Cell Apoptosis by Blocking Caspase-9 Activation in Apoptosome. American Journal of Physiology 289(2):F410-419, 2005.
Wei Q, Yin X, Wang M, Dong Z. Amelioration of Ischemic Renal Injury and Renal Failure in Bid-deficient Mice. American Journal of Physiology 290: F35-F42, 2006.
Wang J, Biju M, Wang M, Haase V, Dong Z. Cytoprotective effects of hypoxia against cisplatin-induced tubular cell apoptosis: Involvement of Mitochondrial Inhibition and p53 Suppression. Journal of American Society of Nephrology 17(7):1875-1885, 2006
Jiang M, Wei Q, Wang J, Du Q, Yu J, Zhang L, Dong Z. Regulation of PUMA-a by p53 in Cisplatin-induced renal cell apoptosis. Oncogene 25: 4056-4066, 2006.
Wang J, Pabla N, Wang C, Wang W, Schoenlein PV, Dong Z. Caspase-mediated cleavage of ATM during cisplatin-induced tubular cell apoptosis: inactivation of its kinase activity towards p53. American Journal of Physiology, 291: F1300-F1307, 2006.
Dong Z, Saikumar P, Weinberg J, Venkatachalam M. Calcium in Cell Injury and Death. Annual Reviews of Pathology 1:405-434, 2006.
Brooks C, Wang J, Dong Z. Characterization of Cell Clones Isolated from Hypoxia-selected Renal Proximal Tubular cells. American Journal of Physiology, 292(1):F243-52, 2007.
Jiang M, Wei Q, Pabla N, Dong G, Wang C, Yang T, Smith S, Dong Z. Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity. Biochemical Pharmacology, 73(9):1499-510, 2007.
Jiang M, Pabla N, Murphy RF, Yang T, Yin XM, Degenhardt K, White E, .Dong Z. Nutlin-3 Protects Kidney Cells during Cisplatin Therapy by Suppressing Bax/Bak activation. Journal of Biological Chemistry, 282(4):2636-45, 2007.
Wei Q, Dong G, Franklin J, Dong Z. The pathological role of Bax in cisplatin nephrotoxicity. Kidney International 72(1):53-62. 2007.
Brooks C, Wei Q, Feng L, Dong G, Tao Y, Mei L, Xie Z, Dong Z. Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with Mitofusins. Proceedings of National Academy of Sciences (USA), 104: 11649-11654, 2007.
