NIEHS Environmental Toxicology Training Program

Professor, Department of Microbiology and Immunology
Role of oxidative stress in aging and allergic inflammation

Reactive oxygen species (ROS) are formed upon incomplete reduction of molecular oxygen and is a collective term that describes clusters of oxygen centered atoms one of which contains an unpaired electron in its outermost shell. ROS cause the toxicity of oxygen and they also operate as cellular signaling molecules, a function that has been widely documented but is still controversial. This controversy stems from the apparent paradox between the specificity that is required for signaling and the reactive nature of ROS that renders them indiscriminate and potentially damaging oxidants. The long-term goal of Boldogh's laboratory is to use multidisciplinary approaches to understand toxicological and signaling effects of environmentally-induced ROS on the immune system and define the basic mechanisms by which reactive species are linked to inflammatory lung diseases. The most exciting new direction of the laboratory is the very recent discovery that: ROS rapidly increased levels oxidative DNA base lesions primarily 8-oxo-7,8-dihydroguanine (8-oxoG); activated 8-oxoguanine DNA glycosylases 1 (OGG1) resulting in release of free 8-oxoG base from DNA. Unexpectedly, ablation of OGG1, but not other DNA base excision repair enzymes (e.g., AP endonuclease 1, Neil-like glycosylases 1 and 2) before oxidative challenge of experimental animals, nearly prevented expression of pro-inflammatory chemokines/cytokines and neutrophil accumulation into airways. Challenge of future studies will be to define cellular signaling induced by 8-oxoG and activation of transcription factors (e.g., NF-kappaB) required for inflammatory gene expression. Understanding molecular linkage between environmental-ROS-DNA damage-repair and inflammatory signaling will provide opportunity developing better treatments to prevent not only lung but other inflammation-based human diseases.

sboldogh@utmb.edu

Professor, Department of Internal Medicine
Roles of glucocorticoid receptor dysfunction, cytokine networking and airway inflammation in asthma

William J Calhoun MD has several principal themes in his laboratory, all of which relate to the role of inflammation and its control in asthma and other airway diseases. First, we are interested in cytokine control of allergic inflammation in asthma. We have made original observations on the role of interleukin-10 as a controller of allergic inflammation. This line of work interfaces with the animal models Dr Ameredes has developed. Secondly, we have novel tools for measuring the function of glucocorticoid receptors [GR]. The regulation of GR by inflammatory cytokines, allergic mediators, oxidants, and anti-inflammatory drugs is a central focus of the laboratory. We have shown that soluble factors from the airway of asthma subjects block GR signaling. Finally, we are also interested in the discovery of biomarkers of asthma severity, and response to therapy in asthma. Using state-of-the-art proteomics in collaboration with Drs Alex Kurosky and John Wiktorowicz, and advanced bioinformatics and biostatistics with Drs Allan Brasier and Suresh Bhavnani, we are searching for predictive biomarkers that distinguish severe asthma from milder forms of the disease, and for biomarkers that predict the response to treatment with steroids or other control medications. Because we are part of two national networks for asthma, we have access to a broad range of clinical samples.

wjcalhou@utmb.edu

Assistant Professor, Department of Preventive Medicine and Community Health
Assessing environmental health effects of toxicants upon human health and quality of life

Sharon A. Croisant (formerly Petronella), MS, PhD, is currently an Associate Professor on the faculty of the University of Texas Medical Branch (UTMB) School of Medicine's Department of Preventive Medicine and Community Health. A doctorally prepared epidemiologist with a master's degree in health promotion and education, she directs the UTMB Center in Environmental Toxicology's Community-based Research Facility as well as its Community Outreach and Engagement Core. She is also a Center investigator within the Institute for Translational Sciences, which houses the University's Clinical and Translational Science Award, where she serves as co-director of the Community Engagement and Research Key Resource. A major focus of her career has been translational or integrative research, i.e., building interfaces between and among environmental and clinical research, education, and community health. She has considerable expertise in Community-Based Participatory Research, including its applications in Environmental Justice communities. She served as a co-investigator in an NIEHS-funded Environmental Justice grant, "Project COAL" (Communities Organized against Asthma and Lead), and is currently funded by the EPA to carry out community outreach in Port Arthur, TX, one of ten nationwide EJ Showcase Communities. She has participated in multiple projects designed to elucidate the causes and mechanisms of asthma exacerbations related to air pollution and has established long-standing, ongoing collaborative relationships with community stakeholders with a vested interest in using these research findings to direct community-based intervention and outreach activities. She has extensive experience in working with diverse committees at local, state, and national levels, to include membership on the National CTSA Key Function Committee and service on numerous study sections for the National Institute of Environmental Health Sciences and the National Center for Research Resources. Until 2009, she served as president of the Asthma Coalition of Texas and as a board member since its inception in 2001. She has worked closely with state policy makers to inform evidence-based environmental and public health legislation.

spetrone@utmb.edu

Associate Professor, Department of Neurology

Targeting the nuclear receptor peroxisome proliferator activated receptor gamma as a means to enhance abstinence
from cocaine abuse.

Addiction is a disease that involves disordered integration of cognitive and motivational aspects of reward-directed behavior induced by the toxic effects of the abused drug. A goal of my lab's work is to accelerate the pace of discovery in addiction research by substantiating a novel, innovative therapeutic strategy to reduce the incidence of relapse in cocaine users through prevention of abstinence-induced neuroadaptations. Peroxisome proliferator-activated receptor gamma (PPARy) is a nuclear receptor best known as a major therapeutic target for type 2 diabetes. The PPARy agonists that fall into the structural class of thiazolidinedione (TZD) compounds, Avandia (rosiglitazone, RSG) and Actos (pioglitazone, PIO), are FDA-approved for treatment of type 2 diabetes; these ligands penetrate the blood brain barrier and have been shown to be neuroprotective in neural injury models such as alcohol abuse, hypoxia-ischemia, and traumatic brain injury. We recently demonstrated that PPARy agonism attenuates cocaine seeking behavior when cocaine self-administering rats are treated with PIO during an abstinence period. Thus, we propose that PPARy agonism is a route to prevent dysregulated neuroadaptations that lead to compulsive cocaine seeking behavior. While these studies validate CNS PPARy as a cocaine addiction clinical target, TZDs have adverse side effects that restrict clinical usefulness, leaving an unmet need for next generation PPARy modulators. Our work aims to discover new, safer therapeutics that target PPARy to improve an individual's chances of maintaining abstinence from cocaine abuse in addition to delineating the molecular players involved in these behavior-modifying actions.

ktdinele@utmb.edu

Professor, Department of Pharmacology and Toxicology
Understanding the molecular mechanisms of Ah Receptor action in toxicity and environmental health risk assessment

The major focus of Dr. Elferink's research is the role of the aryl hydrocarbon receptor (AhR) in liver homeostasis, with an emphasis on the AhR-mediated regulation of cell cycle control. The AhR is a ligand-activated soluble transcription factor historically studied for its role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) induced toxicity. TCDD toxicity however, represents a disruption of normal AhR functions that influence fundamental physiological processes underlying growth and differentiation. Dr Elferink has found in studies using primary liver cells and mouse models that the AhR regulates hepatocyte cell cycle control by regulating G1 phase cyclin-dependent kinase activity. The long-term objectives are to garner a mechanistic understanding of AhR activity in liver regeneration following hepatic injury. These studies hold the promise of identifying new therapeutic targets for the treatment of various liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma (HCC).

In a second research endeavor, the laboratory is actively seeking to identify serum biomarkers for early detection of HCC in Hepatitis C Virus (HCV) infected patients at-risk for developing cancer. The approach involves proteomic strategies based on 2D-difference in gel electrophoresis and stable isotope labeling coupled to mass spectrometry, and multiplexed Selected Reaction Monitoring for use in validation studies. Successful development of serum biomarkers will enhance surveillance of millions who are HCV-positive and at risk of developing HCC.

coelferi@utmb.edu

Associate Professor, Department of Surgery
Mechanisms of neurotoxicity of gaseous and particulate agents in combustion smoke

Acute and chronic exposures to gaseous and particulate agents in combustion smoke generate free radicals, which damage cellular components, including genomic and mitochondrial DNA. Accumulation of oxidative DNA damage has been implicated in etiology of many human diseases and environmental exposures have been strongly implicated in neuronal dysfunction and etiology of various neurodegenerative diseases. Most oxidative DNA lesions are repaired via the Base Excision Repair (BER) pathway, which is the major repair pathway in the brain. Dr Englander investigates the BER pathway and oxidative DNA damage as a direct measurable end point of exposure to combustion smoke in the brain. Dr Englander's goals are to understand the relationship between oxidative DNA damage in neurons, neuronal capacity for damage repair and, to what extent the DNA damage response is consequential to survival and preservation of neuronal function.

elenglan@utmb.edu

Professor, Department of Pediatrics
Innate immunity, oxidative responses and environmental tobacco smoke

The major research interests of Dr. Garofalo's laboratory are the pathogenesis of respiratory syncytial virus (RSV) infection and environmental risk factors for RSV infection. This virus is the single most important viral pathogen causing acute respiratory-tract infections in infants and children worldwide. In addition, RSV-induced severe lower respiratory tract infections (bronchiolitis) in infancy have been linked to both the development and the severity of chronic asthma. A vaccine for RSV has yet to be developed and immunity to natural infection(s) is incomplete, thus repeated attacks of acute respiratory tract illness, ranging from common colds to pneumonia, affect every individual through adulthood. Although premature infants and those with certain underlying medical conditions are predisposed to more severe infections, the majority of infants hospitalized because of serious RSV disease are born at term and otherwise healthy. This has suggested that risk factors, other than those medical-related, are implicated in the pathogenesis of bronchiolitis. In this regard, exposure to environmental tobacco smoke (ETS) may occur in up to 60% of the infants with RSV bronchiolitis in the US, and different studies have pointed to ETS as a major risk factor for the development of severe infection. Dr. Garofalo's laboratory has shown that early inflammatory events characteristic of the "innate" host response are crucially involved in the pathogenesis of acute RSV-induced disease. One elements of the innate immune system is the airway epithelial cell, which is the major target of RSV infection. RSV-infected airway epithelial cells produce a wide variety of regulatory molecules, known as cytokines, which initiate and sustain immune and inflammatory responses in airway mucosa. Therefore, a central hypothesis of Dr. Garofalo's research is that that exposure to tobacco smoke exacerbates airway disease by enhancing or modifying the pattern of production of cytokines and other immunomodulatory and/or inflammatory protein mediators triggered by viral infection. Overall, these studies have important implications for understanding the molecular mechanisms by which biological agents and chemical pollutants interact, leading to the development of asthma and other chronic airway diseases.

rpgarofa@utmb.edu

Professor, Department of Pathology
Oxidative stress and autoimmune disease

One of the long-term goals of Dr. Khan's laboratory is to elucidate the role of reactive oxygen and nitrogen species (RONS) in the development of autoimmune diseases (ADs) induced and/or exacerbated by chemical exposure. Studies are being conducted to delineate the link between oxidative stress and autoimmunity by exposing autoimmune-prone (MRL+/+) mice to trichloroethene (TCE). Formation of lipid peroxidation-derived aldehyde (LPDA)-protein adducts and their corresponding antibodies are being correlated with autoimmune response. Furthermore, studies using sera of systemic lupus erythematosus (SLE) patients show strong correlation of oxidative and nitrosative stress markers with SLE disease activity. Establishing oxidative stress as a pathogenic mechanism of ADs could be important in developing therapies. Another area of Dr. Khan's research is delineation of molecular mechanisms by which aniline or substituted-anilines cause toxicity to spleen. Studies from his lab have shown that aniline exposure leads to time- and dose-dependent accumulation of iron in the spleen of rats, which correlates well with the development of fibrotic lesions. Aniline exposure in rats also showed increases in splenic lipid peroxidation, protein oxidation, DNA oxidation and nitrotyrosine formation, suggesting the role of RONS in the splenic toxicity of aniline. Aniline-induced oxidative stress was also associated with the activation of MAP kinases and transcription factors NF-kB and AP-1, and up-regulation of several inflammatory and fibrogenic cytokines. Dr. Khan is also interested in developing biomarkers of chemical exposure. Recent studies have shown chemical-protein adducts and their corresponding antibodies could be potential biomarkers of exposure.

mfkhan@utmb.edu

Professor, Ophthalmology

I have significant expertise in the areas of bioengineering and imaging and have extensive experience in the development of new imaging and sensing technology as well as in conducting basic and translational research. At UTMB, I have been successfully directing the Center for Biomedical Engineering (CBME), a multi-disciplinary research center with its focus on biomedical imaging, sensing and applications of photonics and imaging in biology and medicine, the Director of the Imaging Division of the Galveston National Laboratory and since 2011 the Vice Chair for research in the Department of Ophthalmology and Visual Sciences. As part of these efforts I have been building interdisciplinary research projects and training programs for graduate and medical students, residents and fellows at UTMB while contributing to the development of several imaging techniques and their applications in the field of medicine. I have 9 patents issued in the areas of biomedical sensing, imaging and thermal therapy. One of my patents covers the application of multimodal imaging using wide field fluorescence imaging to guide high resolution optical biopsy using optical coherence tomography technique. This technology has been developed and commercialized for retinal imaging. In the past several years, I have lead the efforts in the development of non-invasive imaging techniques for in vivo detection, high resolution visualization and grading of microbicides-induced injury in vaginal and rectal mucosa. These techniques have been used to assess and quantify drug toxicity. Furthermore, our group has been highly instrumental in the development and validation of sheep as a large animal model for the evaluation of safety of microbicides as well as the performance of intravaginal rings (IVRs) for microbicides delivery. These efforts have resulted in transition of high resolution imaging techniques for clinical evaluation of toxicity of emerging microbicides and HIV preventive agents that are currently being evaluated in pre-clinical and clinical studies. I have also been working on the development as well as the assessment of safety and toxicity of nanoparticles that have been engineered to be used as vehicles for drug delivery and probes for molecular imaging. In the past five years I have been involved in supervising and training of 5 graduate students, medical students and physician working toward their MS or Ph.D. degree.

mmotamed@utmb.edu

Professor, Department of Human Biological Chemistry & Genetics
Biochemical changes that render aging tissue vulnerable to oxidants

Currently, there are two major research programs in laboratory of Dr John Papaconstantinou. The first, one of four projects in his NIA Program Project "Oxidative Stress, Mitochondrial Dysfunction and Aging" investigates the effects of aging on stress response signaling pathways. Research addresses the proposal that excess amounts of reactive oxygen species [ROS] in aged tissues, produced by mitochondrial dysfunction, affect the function of the p38 MAPK stress response. In support of this proposal, his laboratory has shown age-associated modifications of the p38 MAPK proteins (phosphorylation/cargbonylation) in aged mouse livers that affect their kinase activity and docking. He has also shown that the p38 MAPK pathway in the aged liver fails to respond to ROS caused by mitochondrial dysfunction. This research program involves in-depth analysis of molecular signaling mechanisms in aging tissues and correlation of these processes with age-associated decline in tissue function. The second program in Dr Papaconstatinou's laboratory involves identification of the molecular genetic processes that control longevity in the long-lived mouse dwarf mutants (Snell dw/dw) and Ames (df/df). These mice carry the Pit1 and Prop1 mutations, respectively which results in GH deficiency and dwarfism. The goal is to study whether the Pit1/Prop1 mutations result in a reduction-of-function of the insulin/IGF-1 signaling pathway, and whether this is a basic physiological factor that determines longevity. Furthermore, he proposes to determine whether the Snell and Ames dwarf mice mimic the physiological characteristics of the long-lived nematode (C. elegans) daf-2 mutants, i.e., mutants exhibiting a reduction of function of the daf-2 (insulin/IGF-1 like) signaling pathway. The long range goal is to determine whether the molecular genetics basis of longevity in the mice is similar to that of the nematode.

jpapacon@utmb.edu

Professor and Chair, Department of Pharmacology and Toxicology
Chemistry and biology of DNA damage resulting from both carcinogens and cancer chemotherapy agent

Dr. Sower's work has involved the chemistry and biology of DNA damage resulting from both carcinogens and cancer chemotherapy agents. More recently, we have focused upon damage to DNA resulting from reactive molecules generated by activated inflammatory cells including eosinophils and neutrophils. We have recently demonstrated how certain inflammation-mediated DNA damage products could mimic epigenetic signals, perhaps explaining how inflammation could result in heritable changes in genes expression important for the silencing of tumor suppressor genes in the development of cancer, and how early exposure to agents that trigger inflammation could influence disease susceptibility later in life. Our laboratory has trained numerous Ph.D., M.D. and M.D/Ph.D students over the years and we look forward to training further students within the context of this outstanding and unique translational and interdisciplinary training program in Galveston.

lasowers@utmb.edu

Professor, Department of Neuroscience and Cell Biology
Neurotoxicity in the aged and diseased CNS

The main interest of Dr. Taglialatela's research group is the molecular events mediating neurotoxicity in the aged or diseased central nervous system (CNS). Specifically postulated is that toxicants like misfolded amyloid proteins as the Alzheimer's amyloid beta (Ab) or Parkinson's alpha-synuclein trigger cellular stress responses that become maladaptive in the aged or diseased CNS, thus leading to neuronal impairments and associated neurological deficits. The overarching goal is to systematically identify intrinsic or extrinsic (e.g., environmental) toxicants that impact on those molecular events that lead to improper or maladaptive cellular stress response in aged or diseased neurons so as to obtain fresh insight into new strategies for preventing neurodegeneration. With this goal in mind, Dr. Taglialatela's research group has identified unique events elicited at the synapses by small oligomeric aggregates of amyloid proteins that are dependent on environmental toxicant such as heavy metals and thus amenable to pharmacological targeting for prevention of neurotoxicity. Furthermore, working with banked diseased human brains, his team has recently identified a unique group of individuals who were cognitively intact but presented neuropathological features of severe Alzheimer's disease (Ab oligomers, senile plaques and neurofibrillary tangles). Through the study of these valuable specimens, Dr. Taglialatela's team hopes to unveil the endogenous mechanism(s) that obviously protected these individuals from the neurotoxicity associated with the progression of this terminal neurodegenerative disease so as to identify new pharmacological targets for the development of an effective treatment. Notably, recent findings in Dr. Taglialatela's group have illustrated that contrary to demented Alzheimer's Disease patients, these immune individuals efficiently scavenge neurotoxicant heavy metals within the synapses, thus reducing dysfunctional targeting of the synapse by toxic amyloid oligomers, a phenomenon known to be promoted by intoxicating heavy metal ions.

gtaglial@utmb.edu

Associate Professor, Department of Anesthesiology
Reduction of environmental opportunistic infections in trauma patients through manipulation of innate immunity.

The research in Dr. Toliver-Kinsky's laboratory addresses the immunological perturbations that are induced by traumatic injury and mechanisms by which the immune system can be manipulated to decrease susceptibility to environmental opportunistic infections. Areas studied include inflammatory and effector cell responses to injury, therapeutic modulation of dendritic cells that detect and respond to toxic stimuli and environmental microorganisms, regulation of host responses to endotoxin, and roles of the innate immune system in wound healing. Traumatic injuries, such as severe burns, induce temporary states of immunosuppression and exaggerated inflammation that leave patients susceptible to environmental infections that can lead to severe sepsis. Her research has discovered that a dendritic cell growth factor, fms-like tyrosine kinase-3 ligand (Flt3L), increases resistance to infections after severe injury and prevents uncontrolled systemic inflammatory responses to infection. Enhanced resistance to infections and systemic inflammation is mediated by dendritic cells and neutrophils, immune cells that mediate early responses to environmental pathogens and stress signals. Dr. Toliver-Kinsky's research is focused on how dendritic cells and neutrophils can be manipulated to enhance responses to microorganisms and their toxic products. flt3 signaling pathways in dendritic cells are being investigated, as are the effects of flt3 pathway activation on dendritic cell responses to endotoxin. Another research project in her lab is investigating the roles of neutrophils and dendritic cells in wound healing processes. This translational research utilizes clinically relevant models to assess local and systemic responses by a variety of molecular, cellular, microbiological and immunological techniques. These studies should provide important information on how the innate immune system can effectively respond to nosocomial microorganisms that are common in the trauma care environment, provide the rationale for immunomodulation to decrease susceptibility to wound contamination and to promote wound healing, and increase our understanding of wound healing processes and their regulation by innate immune cells.

ttoliver@utmb.edu

Associate Professor, Department of Pharmacology and Toxicology
Associate Director, NIEHS Environmental 
Toxicology Training Program
Environmental influences on AHR and NF-kB signaling in normal versus autoimmunity.

My research program is focused on studying the contribution of inflammatory signaling to the development and progression of autoimmune diseases, including hematological malignancies. Specifically, we focus on the regulatory mechanisms of two transcription factors that play a role in promoting cancer and autoimmunity, nuclear factor-kappaB (NF-kB) and the aryl hydrocarbon receptor (AHR). We have found a common link between these two pathways and, given that the AHR is a major sensor of xenobiotics, we are committed to understanding how the environment influences the development of autoimmune disorders. Our long-term goal is to better understand how the NF-kB and AHR signaling pathways are regulated on a molecular level in order to identify possible therapeutic targets for the myriad immunological disorders that arise from deregulated signaling.  To achieve our goal we mostly employ molecular, biochemical, and immunological techniques in order to test our hypotheses. I encourage enthusiastic postdoctoral candidates and prospective students with similar backgrounds/interests to contact me regarding available positions in the laboratory.

cawright@utmb.edu