Research Interests
Role of hypoxia, cell signaling and gene regulation
Bryan Copple, Ph.D., a postdoctoral fellow with an NIH Individual Research Service Award at Michigan State University, has accepted a position as Assistant Professor of Pharmacology and Toxicology at KUMC. His research, in general, focuses on cell interactions and signaling in liver pathogenesis.
Dr. Copple's recent studies have focused on understanding the role of low intracellular p02 in the development of hepatic veno-occlusive disease (HVOD), a type of liver fibrosis that occurs in humans exposed to plant-derived pyrrolizidine alkaloids and in patients that receive high-dose, cytoreductive therapy for bone marrow transplantation. The incidence of HVOD in bone marrow transplant units is as high as 64% and the mortality rate ranges from 20-50%, making it one of the leading causes of death in bone marrow transplant patients.
Dr. Copple proposes that the damage to endothelial cells in the liver during early HVOD causes extensive vascular disruption and hypoxia. He suggests that mononuclear phagocytes migrate into these injured regions of the liver, become hypoxic and upregulate hypoxia-inducible transcription factor (Egr-1), which transactivates genes involved in liver fibrosis. These early events lead to the deposition of excess extracellular matrix (i.e., fibrosis).
A second research interest of Dr. Copple is to understand the role of hypoxia and hypoxia-regulated transcription factors in liver repair. He hypothesizes that the hypoxia produced in liver during acute hepatotoxicity promotes upregulation of hypoxia-regulated transcription factors (i.e. Egr-1 and hypoxia-inducible factors [HIFs]) in liver cells and inflammatory cells that accumulate in liver. These transcription factors transactivate and upregulate growth factors and other mediators that promote repair of the liver. Numerous genes regulated by HIFs are involved in repair of the liver, such as TGF-ß3, plasminogen activator inhibitor-1, VEGF and VEGF receptor FLT-1. In addition, HIFs also regulate a variety of genes involved in cell cycle regulation such as p53, p21 and cyclins. A greater understanding of these pathways may provide insight into therapies that enhance liver repair in patients with liver injury and disease.
Dr. Copple's third area of research is to understand the role of bone marrow-derived endothelial progenitor cells (EPCs) in revascularization of the liver after injury. He hypothesizes that EPCs contribute to revascularization of the liver after it is damaged will be tested. Preliminary studies have been initiated to determine whether there is an increase in the number of circulating EPCs in the blood after MCT treatment. If EPCs do contribute to blood vessel formation in liver, these studies will be expanded to identify the signals that promote recruitment, differentiation and division of these cells in liver.
Copple, B.L., Woolley, B., Banes, A., Ganey, P.E., and Roth, R.A. (2002). Anticoagulants prevent monocrotaline-induced hepatic parenchymal cell injury but not endothelial cell injury in the rat. Toxicol. Appl. Pharmacol. 180:186-196.
Yee, S.B., Copple, B.L., Ganey, P.E., and Roth, R.A. (2002). The temporal relationship between bacterial lipopolysaccharide and monocrotaline exposures influences toxicity: Shift in response from hepatotoxicity to nitric oxide-dependent lethality. J. Toxicol. Environ. Health 65:961-976.
Kinder, S., Copple, B.L., Roth, R.A., and Ganey, P.E. (200). Enhancement of allyl alcohol hepatotoxicity by endotoxin requires extrahepatic factors. Toxicol. Sci. 69:470-481.
Luyendyk, J.P., Copple, B.L., Barton, C.C., Ganey, P.E., and Roth, R.A. (2002). Augmentation of aflatoxin B1 hepatotoxicity by endotoxin: Involvement of endothelium and the coagulation system. Toxicol. Sci., in press.
Copple, B.L., Moulin, F., Hanumegowda, U., Ganey, P.E., and Roth, R.A. (2003). Thrombin and PAR-1 agonists promote lipopolysaccharide-induced hepatocellular injury in perfused livers. Accepted for publication in J. Pharmacol. Exp. Ther.
Bryan L. Copple, Ph.D.
Assistant Professor
Department of Pharmacology, Toxicology and Therapeutics
The University of Kansas Medical Center
MS 1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160
Phone: 913-588-7142
Fax: 913- 588-7501
Email: bcopple@kumc.edu
Updated 08/12/2005
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The University of Kansas Medical Center