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| - Overview
- Core Directors and Members
- Key Words
- Research Interests
Led by Dr. Valeria Culotta, Professor of Toxicological Sciences and Dr. Shyam Biswal, Associate Professor of Toxicological Sciences, this core facilitates the investigation of basic mechanistic studies in areas such as oxidative damage including the induction of genes specific to oxidative damage, genetic regulation of superoxide dismutase, mechanisms of lead toxicity, susceptibility to benzene and PAHs and the study of estrogen and androgen mediated effects in biologic systems. Since it is paramount to this Center that our intervention strategies have a mechanistic rationale, this core serves to provide a foundation for our efforts. Core Director and Members Dr. Valeria Culotta, Director and Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health (JHSPH)
Dr. Shyam Biswal, Co-Director and Associate Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health
Dr. Joseph Bressler, Associate Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health
Dr. Terry Brown, Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health
Dr. Robert Casero, Professor
Oncology, Johns Hopkins School of Medicine
Dr. S. Chandrasegaran, Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health
Dr. Anna Mae Diehl, Associate Professor
Johns Hopkins School of Medicine
Dr. Tomas Guilarte, Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health
Dr. Michael A. Trush, Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health
Dr. James Yager, Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health
Dr. Barry Zirkin, Professor
Department of Biochemistry and Molecular Biology
Johns Hopkins Bloomberg School of Public Health DNA damage, Oxidative stress, lead toxicity, molecular toxicology
Barry Zirkin has had a long-standing interest in the mechanisms of Leydig cell aging in the testes and most recently, his research has focused on the role of ROS in this process. Over the past funding period, his research has extended into sertoli cell aging and impacts on cholesterol transport. Michael Trush has devoted much of his career towards an understanding of ROS production, particularly from the mitochondria, and its role in organic xenobiotic toxicity. In a recently published collaboration with James Yager, Dr. Trush has investigated effects of environmental estrogens on mitochondrial function and glutathione. Dr. Trush has also been working with Terence Risby (Gene-Environment Interaction and Disease Prevention Research Core) on induction of heme oxygenase in response to airborne particulate matter. Val Culotta has been exploiting the simple unicellular eukaryote, yeast, as a model system to clone and characterize genes involved in reactive oxygen toxicity. Much of the work she has accomplished over the past year has focused on mitochondrial antioxidant enzymes. This includes an understanding of how the copper/zinc and manganese containing forms of superoxide dismutase (SOD) together provide effective protection against mitochondrial-derived superoxide. In addition, she has uncovered the means by which a single gene can encode both mitochondrial and cytosolic forms of GSH reductase and the mechanism appears conserved in yeast and humans. She has also been assisting Dr. Yager in his studies on mammalian SOD2 mutations as a possible risk for breast cancer. In addition, she has worked closely with Dr. Biswal (Molecular Toxicology Research Core) in monitoring changes in gene expression profiles as a function of oxidative stress in yeast. Jim Yager has been focusing on the mechanistic role of endogenous and environmental estrogen-compounds in cancer. His research on oxidative metabolism of estrogen molecules has been extrapolated to population studies where he has discovered exciting links between polymorphisms in COMT (catechol-O-methyltransferase, a key metabolic enzyme for catechol estrogens) and breast cancer risk. In addition, he has recently initiated investigations on polymorphisms on mitochondrial SOD2 and possible links to breast cancer, studies which, as mentioned above, involve collaborations with Dr. Culotta and Trush. Very recent work has demonstrated a novel transport of the estrogen receptor into mitochondria, providing a novel link between mitochondrial ROS induction and environmental estrogens. Bob Casero has made some interesting breakthroughs in the role of polyamines in protecting against oxidative stress induced apoptosis. Dr. Casero's laboratory has very recently published the roles of polyamines in chemoprevention, work that has been a collaborative effort with Dr. Kensler (Gene-Environment Interaction and Disease Prevention Research Core). These researchers have demonstrated that polyamines regulate the anti-oxidant response transcription factor Nrf-2, and therefore polyamines represent a novel endogenous inducer of anti-oxidant and phase II detoxification enzymes.
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Dr. Michael Trush has a great interest in Benzo(a)pyrene (BP) metabolism and quinone toxicity. BP is a ubiquitous environmental pollutant produced by industrial and transportation sources and is therefore of great concern in urban settings. It is also present in cigarette smoke and foods, which account for important sources of human exposure. In the past year, Dr. Trush has published some interesting findings on acrolein toxicity and induction of GSH-S tranferases. Dr. Shyam Biswal is extensively working in genome wide responses to urban pollutants and components of cigarette smoke such as acrolein. He is currently using a toxicogenomics approach to identify changes in gene expression resulting from exposure to different environmental electrophiles, including acrolein. Since Dr. Biswal joined the Department, he has initiated several interactions with members of the NIEHS Center, including Tom Kensler Gene-Environment Interaction and Disease Prevention Research Core (gene profile studies in Nrf2 knock out mice), Jonathan Links and Tom Guilarte (lung tumor monitoring through PET scanning) Cellular and In Vivo Imaging and Analysis Facility Core and P. Lein (protein phosphorylation responses to electrophiles; Molecular Toxicology Research Core). In addition, he has a recent publication with Drs. Mitzner and Wagner (Environmental Lung Disease Research Core) regarding transcriptional profiling in the airway. The NIEHS Center has been very instrumental in launching Dr. Biswal's program, through support from pilot project grants, to strong use of Core facilities (DNA, microscopy, imaging). Dr. Pam Lein's research program has focused on the effects of toxins and growth factors on dendritic growth in cell culture and in intact animals. Much of her work has addressed on effects of PCBs and organophosphate xenobiotics. Her work on pesticides is particularly relevant to urban settings where in-house insect problems are very prevalent and over the past year she has published work on organophosphate insecticides through collaborations with Dr. Fryer and Jett (center members that recently left the university). Dr. Anna Mae Diehl focuses on liver disease and regeneration. Liver regeneration is essential for recovery from all injuries that destroy hepatocytes. Dr. Diehl has published a number of studies over the past year that address the effects of alcohol in liver disease, particularly in models of obesity.
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Dr. Culotta has been investigating the mechanisms of metal ion metabolism and metal ion toxicology. Most recently, her attention has been drawn to manganese, a potent neurotoxin and component of gasoline. Over the past year, she has noted that cellular uptake of toxic manganese is largely mediated through the phosphate transporter. She has also addressed the mechanism by which mitochondria take up manganese for incorporation into the manganese containing superoxide dismutase. Dr. Bressler has had a long-standing interest in the metabolism of lead and the signaling events following exposure to lead. Dr. Bressler is a member of the EHS faculty and also the Kennedy Krieger Center, which has a major focus on lead toxicity in children. Over the past year, he has published findings on the role of the divalent metal transporter DMT1 and lead transport, studies which were fostered through a collaboration with P. Lees (Environmental Epidemiology and Exposure Assessment). In addition, he has uncovered new roles of protein kinase C and signaling following exposure to lead. Dr. Guilarte has also had a major interest in lead, particularly regarding its effects on the NMDA receptor in mammalian brains. Over the past year, he has published a number of studies that extend from basic biochemical effects on the receptor and protein kinases to changes in learning and behavior as end points. Dr. Guilarte's work has heavily relied on the imaging facilities sponsored by the NIEHS center.
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DNA is a key target for a variety of environmental and endogenous toxicants. The contribution of such damage to cancers and the aging process is well documented. Three members of the faculty represent the DNA damage /repair arena of toxicology: C. Pickart, BMB, K. Singh, Oncology and L Grossman (BMB). Dr. Grossman has recently retired, although continues to be active on campus and provides invaluable intellectual input to the community. Over the past year, he has published findings connecting DNA damage repair defects and skin cancer in Puerto Rican populations.
Dr. Keshav Singh from Oncology focuses on DNA damage and repair pathways in both yeast and humans. As a novel niche, Dr. Singh has been focusing on damage to mitochondrial DNA and its relationship to cancers and has recently published several new findings on DNA damage specific to this organelle.
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Dr. Yager has long been investigating the role of endogenous and environmental estrogen compounds in various cancers. Estrogenic compounds can induce changes in gene expression either directly by binding to the estrogen receptor (ER) or indirectly through metabolism to more reactive compounds (as described above for ROS toxicity). In a very recent publication, Dr. Yager finds that estrogens activate mitochondrial gene expression. In fact, he has compelling evidence for the localization of the ER within the mitochondria where it can directly induce the transcription of mitochondrial genes. With the linkage of mitochondria to cellular process such as apoptosis and cancer, these findings are highly significant.
As mentioned above, Dr. Zirkin focuses on age-related changes in the male reproductive tract. In addition, Dr. Zirkin has been collaborating extensively with Dr. T. Brown in probing the effects of androgen ablation on the prostate.
Dr. T. Brown focuses on the role of androgens in cancer and hyperplasia of the prostate. Much of his work has addressed the transcriptional machinery that plays a critical role in modulating androgen receptor activity and recently, he has reported on the role of Nf-KB in androgen receptor activation. Dr. Brown has received funding from a pilot project from the NIEHS center to examine age related changes in gene expression profiles of the prostate.
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