Toxicology

NIEHS Training Grant in Molecular Mechanisms of Toxicity

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The research activities of the entire faculty address fundamental molecular and cellular mechanisms of toxicity, and importantly, the prevention of toxicity/disease induced by environmental agents. One important focus of the Training Grant Faculty is to enhance our understanding of the role of dietary modulators and nutritional factors in the molecular control of reactive oxygen and nitrogen species in initiation and progression of environmentally induced disease processes such as cancer and cardiovascular disease. An additional key focus is the role of DNA damage and repair induced by classic environmental carcinogens, UV-radiation and oxidative stress, in the development of toxic endpoints, primarily cancer, but is also now recognized as a component of neurodegenerative disease. These themes serve to provide opportunities for interactions and in-depth interdisciplinary approaches to research problems. While individual faculty are grouped under specific subheadings for description of their research programs, many of these investigators combine several of these themes in their individual research programs. The result is a rich and fertile environment for the training of pre- and postdoctoral fellows who can draw on this breadth and expertise by participating in these research programs.

CANCER: 
Dr. Xianglin Shi:  Dr. Shi's research program is mechanistically based and designed to characterize the linkage between diet, nutrition and environmentally induced oxidative stress (i.e., tissue injury) and disease. 

Dr. Daret St. Clair’s research has been focused on investigating the fundamental mechanisms by which ROS and reactive nitrogen species (RNS) contribute to normal tissue injury and cancer formation in order to develop novel strategies for intervention.  These projects involve evaluating genetic abnormalities of antioxidant enzymes, the mechanisms regulating gene expression, and the impact these alterations have on the ability of humans to cope with oxidative stress generated from chemical carcinogens and environmental agents. 

Dr. Mary Vore’s research is focused on characterization of the function and regulation of expression of the organic anion transporters, particularly the ATP-Binding Cassette (ABC) efflux transporters that mediate the cellular efflux of glutathione and glucuronide conjugates of endo- and xenobiotics, and are thought to function in the elimination of end-products of metabolism.

Dr. Christian Paumi is working to determine the role of the multidrug resistance-associated proteins (MRP, ABCC) in metabolic quality control and cancer. Recent findings by Dr. Paumi suggest that casein kinase 2 (CK2) plays an important role in regulating MRP1 (ABCC1)-associated multidrug resistance (MDR) in cancer.  These studies have direct implications for understanding of the role of the MRPs in cancer and toxin disposition, i.e., heavy metals such as Cd, As or Se. 

Dr. Hsin-Sheng Yang’s research is focused on cancer, specifically colon cancer.  Colorectal cancer is the second most fatal cancer in the US, largely due to invasion and metastasis to the liver and lymph nodes, and arises from somatic genetic changes that involve activation of oncogenes and/or inactivation of tumor suppressor genes. Dr. Yang is focused on characterization of Programmed Cell Death 4 (Pdcd4), a novel tumor suppressor that is frequently down-regulated in several types of cancer.  In colon cancer tissues, expression of Pdcd4 is continuously down-regulated, i.e., normal>adenoma>carcinoma.  Over-expression of Pdcd4 inhibits tumor promoter-induced transformation and tumor phenotype in both cultured cells and mice.

Dr. Howard Glauert is investigating the mechanism of carcinogenesis by environmental agents and the influence of nutrition.  Several diverse environmental chemicals, including phenobarbital, peroxisome proliferators, and PCBs, have tumor promoting activity in the liver. 

Dr. Brett Spear’s research focuses on transcriptional regulation in the liver during development and disease, and emphasizes the use of genetically-modified mouse models.  Historically, his research has focused on transcriptional repression during postnatal liver development and has used alpha-fetoprotein (AFP) as a model system.  AFP is an ideal gene for this purpose, since it is expressed at high levels in the fetal liver, silenced at birth, and re-activated during liver regeneration and in liver cancer.  The Spear lab is working on the relationship between oxidative stress, liver cancer, and transcriptional control in collaboration with Dr. Howard Glauert. 

Dr. Natasha Kyprianou’s research is focused on urologic oncology and prostate cancer, primarily on the genetic regulation of apoptotic and growth factor signaling pathways in prostate cancer.  Her laboratory has two main directions: (1) characterization of the impairment of the signaling network operated by the multifunctional cytokine, transforming growth factor-β (TGF-β), during prostate cancer progression, and 2) the resulting loss of apoptosis and cell cycle regulation in prostate cancer.  She uses proteomic approaches to study novel TGF-β signaling effectors in apoptosis in prostate cancer cells (in collaboration with Dr. Haining Zhu), and to investigate the mechanisms of androgen receptor signaling deregulation contributing to the development of hormone-refractory prostate cancer. 

Dr. Vivek Rangnekar’s laboratory is investigating the molecular cross-talk between oncogenes and tumor suppressor genes in an effort to tilt the balance in favor of tumor suppressor gene expression or function. Dr. Rangnekar discovered the multi-faceted tumor suppressor protein Par-4, and has shown that its up-regulation induces apoptotic death specifically in cancer cells, while its absence leads to tumor growth and depression in mouse models. 

Dr. Hollie Swanson’s laboratory is focused on 1) understanding how exposures to environmental contaminants that act as aryl hydrocarbon receptor (AHR) agonists contribute to human diseases, in particular cancer and 2) demonstrating that blocking the AHR can be an effective approach to be used for the treatment of relevant human disease states.

Dr. Joy Zhang’s research focuses on mechanisms of toxicity and carcinogenesis induced by metals such as arsenic, cadmium, nickel, and chromium and the role of metal-induced oxidative stress in regulating cell migration and invasion, transformation, angiogenesis, tumorigenesis, cell cycle, and apoptosis.  Her research interests also include mechanism-based prevention and control of environmental disease by investigation of the antioxidant properties of various naturally occurring antioxidants and to develop these as chemopreventive agents against metal- or UV-induced carcinogenesis.

Dr. Guo-min Li's laboratory is focused on how DNA repair mechanisms play roles in preventing human diseases, including cancer, aging and neurodegenerative disorders. A longstanding project in Dr. Li’s laboratory is DNA mismatch repair (MMR), a critical cellular mechanism that maintains genomic stability by both correcting mismatches generated during DNA metabolism (replication, combination and repair) and mediating apoptosis of cells with severe DNA damage caused by physical and chemical reagents, including environmental carcinogens.

Dr. David Orren's laboratory studies DNA damage, genomic instability and the cellular enzymatic pathways that minimize their deleterious effects on human health including cancer and other phenotypes associated with aging. One project investigates the WRN-and other RecQ helicase-dependent pathways that act in telomere maintenance and proper resolution of replication blockage.

Dr. Liya Gu’s research focuses on mechanistic studies of DNA repair in human cancer and aging. One of her projects studies leukemogenesis and relapse. Her laboratory has recently demonstrated that both persistent (initially resistant to chemotherapy) and relapsed (acquired resistance) leukemias are closely associated with defects in DNA MMR.

Dr. Zhigang Wang’s lab is focused on DNA damage-induced mutagenesis and its role in carcinogenesis.  Using various mouse tumor models, Dr. Wang’s lab examines if deleting the Rev1 gene in mice will indeed prevent various types of cancer such as lung cancer, skin cancer, pancreatic cancer, and liver cancer. 

Dr. Tadahide Izumi’s research is focused on DNA damage and mutagenesis, specifically those generated by reactive oxygen species (ROS).  Oxidative DNA damage is generated by internally produced ROS and exogenous DNA damaging reagents, such as ionizing radiation.. DNA base excision repair (BER) is indispensable for normal cells to keep the genomic integrity intact against the continuous attack from ROS.  Apurinic/apyrimidinic endonuclease (APE1 in mammals) is a pivotal BER enzyme that also modulates the cellular redox state and regulates important transcription factors such as AP1, p53 and NF-kB via their reduction. Dr. Izumi’s lab currently focuses on how the activity of APE1 is regulated by post-translational modification including oxidation/reduction and ubiquitination.

Dr. John D’Orazio’s laboratory is focused on defining mechanisms by which UV radiation promotes mutagenesis and carcinogenic transformation of melanocytes, with a specific focus on the role of the melanocortin 1 receptor (MC1R), a transmembrane Gs-coupled receptor.

Dr. Qiou Wei is investigating how reactive oxygen species (ROS) contribute to carcinogenesis and cancer progression. The scope of research includes study of (1) intracellular signaling events mediated by ROS and environmental carcinogens, (2) unique molecular indicators of oxidative stress, and (3) understanding how these contribute to tumorigenesis, tumor promotion and cancer progression. Current research is focused on elucidating the molecular mechanism by which Sulfiredoxin, a novel oxidative stress induced redox enzyme, promotes invasion and metastasis of human cancer cells.

Dr. Gang Chen is investigating the mechanism for metal carcinogenesis, specifically arsenic-induced carcinogenesis and the role of autophagy. 

Dr. Jia Luo is investigating in the cellular/molecular mechanisms underlying 1) ethanol-induced neuronal death, impaired cell cycle kinetics and disrupted cell migration in the developing brain and 2) how ethanol functions as a tumor promoter, particularly in the metastasis of breast cancer cells.   

CARDIOVASCULAR DISEASE: 

Dr. Bernie Hennig’s research is related to the effects of nutrients on biochemical and molecular mechanisms of vascular endothelial cell function, injury, and protection.  His studies are focused on the role of polychlorinated biphenyls (PCBs) in induction of inflamamtory events in endothelial cells in relationship to the development of atherosclerosis. 

Dr. Lisa Cassis has a long standing research interest in the link between obesity and cardiovascular disease, which is the primary cause of death in the obese population.  She has established that coplanar PCB ligands of the arylhydrocarbon receptor (AhR), which accumulate markedly in adipose tissue, increase adipocyte differentiation and proinflammatory gene expression.

Dr. Alan Daugherty’s research seeks to identify the mechanisms of angiotensin II (AngII)-induced abdominal aortic aneurysm (AAA) formation using an integrated approach of vascular and molecular biology, genetics, and biochemistry.  Specifically, his research is focused on the hypothesis that AngII can initiate AAA formation through activation of angiotensin type 1 receptor regulating the low-density lipoprotein receptor-related protein (LRP)-urokinase-type plasminogen activator (uPA) axis to promote medial macrophage accumulation in smooth muscle cells.  In addition, his studies involve determination of the relative importance of the systemic versus local renin angiotensin system (RAS) in the development of atherosclerosis.

NEURODEGENERATIVE DISEASE: 

Dr. Robert Yokel’s research focuses on metals, particularly those that contribute to neurodegenerative disorders. Recently completed work addressed the influx and efflux of manganese across the blood-brain barrier and mediating mechanisms, and the oral bioavailability of aluminum, a suggested contributor to Alzheimer’s disease. Another ongoing funded project is assessing the physico-chemical properties of nanoscale ceria that influence its distribution into the brain and effects on the blood-brain barrier and brain. Engineered nanoscale ceria is being studied as a model engineered nanomaterial and because it is in commercial use as a diesel fuel additive, resulting in its release into the environment, with unknown potential effects.  

Dr. Don Gash’s research focuses on neurodegenerative changes in the nonhuman primate and human brain, including analyzing the role of environmental neurotoxins in initiating and/or exacerbating disease processes.  Dr. Gash is specifically interested in developing and testing new therapeutic approaches to effectively deliver drugs to the brain to slow down and even reverse degenerative changes.  Dr. Gash’s current studies, funded by both NIH and pharmaceutical companies, involve (1) developing GDNF-like trophic peptides for treating Parkinson’s disease, and (2) evaluating siRNA suppression of huntingtin expression in the nonhuman primate striatum as a possible treatment for Huntington’s disease.  These studies are multidisciplinary, including conducting extensive behavioral testing, experimental neurosurgery, MRI brain scans, in vivo microdialysis in awake animals, and quantitative morphological assessment of neural restoration.     

Dr. John Slevin is an active clinician who also conducts basic, translational and clinical research with collaborators across the UK Medical Center.  His translational and clinical research interests focus on the etiology, pathophysiology and treatment of movement disorders, particularly Parkinson’s disease (PD).  In collaboration with Dr. Don Gash, and others, Dr. Slevin is systematically evaluating a group of subjects who experienced chronic occupational exposure to trichloroethylene (TCE); some of these individuals have developed PD and others have shown suggestive signs and symptoms although they do not yet meet criteria for diagnosis. 

Dr. Ed Kasarskis is an active clinician and an ALS expert neurologist focused on movement disorders, specifically Amyotrophic Lateral Sclerosis (ALS).  ALS is a human neurodegenerative disease that is multifactorial in its etiology, with a combination of genetic predisposition and an inciting set of environmental factors.  While some cases of ALS (~10%) are clearly genetic with an autosomal dominant pattern of inheritance linked to mutations in certain genes (SOD1, TDP43, FUS/TLS and others to be identified), the majority of cases are sporadic.  Several potential environmental factors have been linked to ALS, including agricultural chemicals, lead exposure, diet, smoking and military service.  Dr. Kasarskis is leading a team of experts in epidemiology, genetics, and biostatistics to develop a combined regional/state based ALS registry comprising Kentucky and Tennessee as a means to developing a National ALS Registry. 

Dr. Haining Zhu utilizes proteomic, biochemical and cell biology approaches to study neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease).  Mutations in the antioxidant protein copper-zinc superoxide dismutase (SOD1) have been found in a subset of familial ALS patients. Dr. Zhu’s research is focused on elucidating the neurotoxicity of the mutant variants of SOD1. The hypothesis to be tested in his lab is that the mutant SOD1 protein can form aggregates associated with mitochondria and disrupt mitochondrial function. Recent results in his laboratory also suggest that mutant SOD1 can interfere with axonal transport in neurons, the process that is critical to mitochondrial dynamics (trafficking, fission and fusion). Interference with axonal transport thus can lead to abnormal mitochondria morphology and function. This hypothesis is currently being tested by a combination of genetic, biochemical and cell biology approaches.