Igor Zelko, Ph.D., Assistant Professor
Dr. Zelko graduated from Byelorussian State University in 1990 with a master degree in biochemistry. He earned his Ph.D. degree in Chemistry from Byelorussian Academy of Sciences in 1996. He received his post-doctoral training in National Institute of Environmental Health Sciences and worked as Research Associate in the Division of Allergy, Pulmonary and Critical Care Medicine at Duke University. Dr. Zelko joined Duke University as an Assistant Professor from 2005-2007. He recently joined the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Disorders Medicine as an Assistant Professor in August 2007.
Research Interests: Dr. Zelko's current research interests are primarily related to the role of oxidative stress in development of lung and cardiovascular diseases. The main focus of my research has been on the role of extracellular superoxide dismutases (ecSOD) in protection against oxidative stress. Recently we found that expression of mouse and human ecSOD is regulated by several transcription factors including Sp1 and Sp3.
Molecular mechanisms which regulate ecSOD gene expression. The genomic structure of the murine ecSOD gene containing 2 exons and 1 intron is shown. We found that Sp1/Sp3 transcription factors essentially function to promote basal ecSOD transcription. In lung fibroblasts, where ecSOD expression is high, Ets and Sp1/Sp3 transcription factors via a physical interaction with co-activator molecules result in enhanced ecSOD transcription. In the kidney medulla cells, expressing ecSOD at very low level, the transcription factors Kruppel and/or MZF-1 function to repress ecSOD transcription perhaps by recruiting co-repressors or by blocking Sp1/Sp3 activation
Currently, Dr. Zelko is working on several projects described below:
First Project: Role of epigenetic factors in regulation of extracellular superoxide dismutase expression in pulmonary vascular cells.
ecSOD is a the main antioxidant in the vascular wall and is involved in detoxification of harmful oxygen radicals in extracellular space. Vascular ecSOD ecSOD is a the main antioxidant in the vascular wall and is involved in detoxification of harmful oxygen radicals in extracellular space. Vascular ecSOD localized mostly in the space between endothelium and smooth muscle cells, where it concentration might be 3000 times higher than in surrounding spaces. There it regulates concentration of superoxide radicals and therefore control the flow of endothelium derived nitric oxide which stimulates vessel relaxation. hus ecSOD plays a major role in regulation of nitric oxide bioavailability and blood pressure. It also involved in development and progression of atherosclerosis, hypertension and vascular dysfunction. Despite its importance little is known about cell-specific transcriptional regulation of ecSOD in the vessels and the role of DNA methylation in this process. It has been shown that ecSOD expressed at relatively high levels in vascular smooth muscle cells with little expression in endothelial cells. The main goal for this project is to determine mechanism for this cell-specific expression of ecSOD in pulmonary vascular wall. We hypothesised that ecSOD cell-specific expression is regulated by methylation of cytosines in DNA that encode this enzyme.
Epigenetic factors regulating expression of ecSOD. We are proposing that several epigenetic factors such as acetylation/ deacetylation of histones and methylation / demethylation of DNA within ecSOD promoter region regulating its cell-specific and inducible expression.
Dr. Zelko examining specimens under the microscope
Second Project: Role of hyaluronan and oxidative stress in the development of bleomycin induced pulmonary fibrosis.
Bleomycin is a chemotherapy agent widely used for the treatment of certain types of cancer. Unfortunately, up to 2% of patients treated with bleomycin develop symptoms of pulmonary dysfunction and pulmonary fibrosis. Currently there are no effective treatment strategies for patients with lung fibrosis making it one of the most devastating complications seen in patients that undergo chemotherapy. The pathogenesis of bleomycin-induced lung injury is not well understood, but it has been shown that an increased production of reactive oxygen species from bleomycin-iron complexes in the lung procdues a subsequent imbalance of increased oxidants and decreased antioxidants in pulmonary tissues. It is postulated that this inbalance may be responsible for the progressive development of unresolved inflammation and fibrosis, ecSOD is one of the main antioxidative enzymes in lung tissue and protects pulmonary cells from deleterious effects of reactive osygen species.
Chemical sructure of bleomycin. Bleomycins are a group of related basic glycopeptides which differ in the terminal amine substituent of the common structural unit, Bleomycin acid. The main components of Bleomycin for Injection are Bleomycins A2 and B2. Chemically, Bleomycin A2 is N1-[3-(dimethylsulfonio)propyl]-Bleomycinamide and Bleomycin B2 is N1-[4-(aminoiminomethyl)amino]butyl]-Bleomycinamide.
This enzyme is expressed at very high levels in human and mouse lungs and is localized inextracellular matrix where it interacts with heparin and collagen through its C-terminal domain. Hyaluronan is a major extracellular matrix substance to which cells are embedded. Under physiologycal conditions, it exists in the lung as a highly polymerized glycosamingoglycan. Reactive oxygen species produced in response to byelmycin exposure interact with hyaluronan to produce smaller polydispersed fragments. Thus, on one hand, hyaluronan serves as an antioxidant by deactivating oxygen radicals while, on the other hand, its small size fragments promote inflammation of lung tissue and infiltration of immune and collagen producing cells.Our research effort are aimed at finding the interplay between hyaluronan polymerization status and levels of ecSOD in pulmonary interstitium. We haope that these studies will provide additional insights into the mechanism of bleomycin induced lung injury and possibly identify new targets for preventative and therapeutic interventions that will benefit the growing number of cancer patients in this country who undergo chemotherapy.