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Associate Professor, Department of Preventive Medicine and Community Health
Genetic susceptibility to toxic effects of tobacco smoke toxins and other environmental carcinogens
The research program of Dr. Abdel-Rahman focuses on understanding the influence of genetic polymorphisms (inherited genetic DNA sequence variations) on human sensitivity to environmental agents and on response to therapeutic drugs. As PI and co-I on several previously and currently funded research projects he developed novel approaches for understanding the biological and the functional significance of genetic polymorphisms using biomarkers of exposure, susceptibility, and biological effects. The research program, which incorporates bioinformatics, molecular biology, toxicology and pharmacology, has significant translational implications in the areas of environmental health and clinical and cancer research. A primary goal of the research program is to improve our ability to estimate disease risk in exposed populations and deliver on the promises of personalized medicine.
Associate Professor, Preventive Medicine and Community Health
Director, NIEHS Environmental Toxicology Training Program
Mechanisms of functional resolution of allergic airway inflammation and asthma, through molecular and cell-signaling pathways involving IL-10, NO, and beta-receptors
The role of environmental toxicants, such as gaseous and particulate air pollutants, in promoting airway inflammation and hyperresponsiveness may be important in the development of asthma and chronic obstructive pulmonary disease. Our studies include the role of sulfur dioxide (SO2) in animal models and human cell cultures, with focus on the production of reactive oxygen species and subsequent intracellular signaling as the driving force behind the development of airway inflammation in response to environmental pollutants. An important cytokine in the inflammation resolution may be IL-10, which is known to be inhibited in asthma, and may be a reason for the sensitivity of asthmatics to SO2, as compared to non-asthmatics. Utilization of IL-10 knockout mice models this situation, allowing testing of this hypothesis and investigation of its origins. Also of interest are the effects of carbon monoxide (CO) on airway inflammation, potentially through this same cytokine effect node, and its association with nitric oxide (NO) produced within the airway.
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Professor, Department of Pathology
Lipid and protein adducts of xenobiotics and biomonitoring
The major goal of Dr. Ansari's research is to elucidate molecular mechanisms of toxicity of halogenated hydrocarbons, amine and alcohols. Covalent binding to proteins is being studied as potential mechanisms of toxicity. Two aspects of the adduction of environmental chemicals to proteins are of interest. First, adduction to circulatory proteins is examined in order to identify biological markers of exposure. Second, adduction to cellular proteins is being investigated as a mode of potential toxicity. Cellular protein adducts have the potential to act as neoantigens which stimulate autoimmunity and may ultimately cause autoimmune diseases. Current studies of Dr. Ansari have shown that low dose chronic exposure to environmental contaminant trichloroethene causes systematic lupus erythematosus (SLE)- like disease with multi- organ involvement including liver in an autoimmune- prone female mouse model. The role of protein adduct of trichloroethene was established when synthesized albumin adduct of putative metabolite mimicked the autoimmune hepatitis as observed in chronic exposure to trichloroethene. Recently, Dr. Ansari started working on the mechanism of alcoholic fatty liver using systems biology approaches. His lipidomic studies have shown that probably plasma lipidome could serve as a biomarker of alcoholic fatty liver disease.
Professor, Department of Human Biological Chemistry & Genetics
Role of lipid-derived aldehydes in ocular injury
Dr. Ansari has a long-standing interest in the role of lipid-derived aldehydes (LDAs), the reactive and cytotoxic end products of lipid peroxidation, in oxidation-induced pathologies. Her research is based on the hypothesis that LDAs such as 4-hydroxynonenal (HNE) extend oxidative injury in the tissues by causing modifications to membrane proteins (including gap junction and channel proteins) altering membrane fluidity and calcium homeostasis which result in apoptosis and thereby tissue damage. Her studies have demonstrated that oxidative detoxification of HNE, catalyzed by aldehyde dehydrogenase 1(ALDH1A1), is a crucial pathway to protect the tissues against oxidation-induced toxicity because silencing this enzyme increased oxidation-induced toxicity while over expression decreased it. Dr. Ansari's lab is also investigating metal-associated oxidative toxicity and development of effective chelation therapies against oxidative /inflammatory pathologies. Another aspect of her research involves investigating the involvement of ALDH1A1 and HNE in the chemoresistance in cancer stem cells. In summary,her lab is studying the role of ALDH1A1 and intracellular regulation of HNE and signaling in various pathologies to obtain critical insights into the mechanism s by which these aldehydes propagate and mediate oxidative injury to the tissues.
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.
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Professor, Department of Pathology
Influences of amines and aging on cardiovascular pathology
The laboratory of Dr. Boor is interested in how the larger blood vessels of the body are injured by toxic chemicals in our environment. Focus in on injury to the muscular wall of these blood vessels, or the "media." Experimental drugs and other chemicals that protect against such injury - or predispose to injury - are under investigation in the hope that someday we may be able to manipulate the blood vessel wall to delay the commonest degenerative diseases that result in great human morbidity and mortality, including atherosclerosis and aneurysm. Specifically, Dr Boor's laboratory has been defining the cellular and biochemical events that occur during vascular injury by toxic chemicals that are relevant to the environment, or to cigarette smoke components. Past emphasis has been on the metabolism of vasculotoxic amines to aldehydes, while recent work has defined how glutathione-S-transferases act in the defense of vascular wall against reactive molecules both in vivo and in vitro. Important contributions to the understanding of the role played by coronary arterial vasospasm in myocardial injury have been made. The role of these defense mechanisms during cellular injury of the vascular wall by atherosclerosis has also been recently examined. New directions have been undertaken into the area of "developmental vasculotoxicity." Perhaps the most exciting new direction of the laboratory has been the very recent development of a model of dissecting aortic aneurysm. Initial studies into this small animal model have revealed several pathways of fibrillogenesis of collagen and elastin that may prove to be targets of toxic insult early in life, or even during embryologic development, resulting in this deadly disease which is just now coming to be recognized as a common killer of young persons. Hence, Dr Boor's studies delve into the most basic phenomena underlying aging, aneurysm formation, and the atherosclerotic process.
Professor, Department of Human Biological Chemistry & Genetics
Modulation of NF-kB signaling by oxidants and viral infection.
Research by Dr. Brasier addresses how cells transduce environmental signals into temporal changes in gene expression. Environmental signals induce the activation of of DNA-binding proteins controlling the innate inflammatory response in an reactive oxygen species (ROS)- dependent manner. These transcription factors include nuclear factor-kB (NF-kB), a transcription factor that activates expression of genetic networks that play a dominant role in human disease states, such as vascular inflammation and asthma. Dr. Brasier's laboratory has demonstrated how vascular inflammation is mediated by angiotensin II-induced NF-kB signaling and how the pulmonary cytokine cascades are elicited by NF-kB in response to acute respiratory virus infection. Dr Brasier's work has shown that redox-sensitive pathways control NF-kB signaling by inducing serine phosphorylation of the transactivating NF-kB/ Rel A subunit, mediated by either the catalytic subunit of protein kinase A or the mitogen and stress-inducing kinase (MSK). Inhibition of this ROS pathway does not prevent NF-kB translocation, but does inhibit activation of of subset of downstream NF-kB dependent target genes. Work by Brasier's laboratory have shown that these genes are controlled by the PTEF-b transcriptional elongation complex. Another area of current investigation is the novel recent finding that delayed-onset waves of NF-kB dependent gene expression are induced after the nuclear appearance of NF-kB/ Rel A. This pathway appears to be controlled by the production of a specific TRAF isoform Understanding how inflammation is produced by ROS-NF-kB pathway provides insight into how many environmental agents produce common human diseases, and designing better treatments to prevent these diseases.
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.
Associate Professor, Department of Pharmacology and Toxicology
Role of cAMP and oncogene RAS-mediated cell signaling in environmental toxicology
The Cheng laboratory has been using multidisciplinary approaches, coupling biochemistry and biophysics with cell biology and pharmacology, to understand the structure and function of exchange protein directly activated by cAMP (Epac) and oncogene KRAS. Our long-term goals are to unravel the signaling intricacies of Epac and KRAS and to design pathway specific inhibitors for these important signaling molecules so that their functions can be pharmaceutically exploited and modulated for the treatment of human diseases.
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.
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.
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.
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.
The role of environmental toxicants in promoting epithelial cell growth may be important in the development of prostate and other cancers. We are examining an innovative mechanism of action for the environmental toxicant arsenic in the prostate, that of modification of the tumor stroma. Our work points to a novel stromal-related paracrine mechanism for prostate tumor promotion involving migration of mesenchymal/stromal stem cells (MSC) into prostate tumors. We have shown that MSC are typically attracted to prostate tumor cells in vitro and in vivo potentially enhancing malignant paracrine communication with epithelial cells to accelerate tumor growth. Recent evidence suggests that normal cells treated with arsenic can promote abnormal growth of co-cultured prostate epithelial cells, suggesting paracrine mechanisms can mediate the effects of arsenic in the prostate. Arsenic-treated MSC are 'reprogrammed' and have aberrant protumorigenic gene expression profiles. Characterization of the effects of Arsenic exposure on stromal MSC should enable us to begin to devise strategies to prevent MSC from migrating to tumors and/or targeting the reprogrammed MSC to reduce their protumorigenic potential.
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.
Professor, Department of Pediatrics
Environmental influences on allergic mucosal inflammation, particularly pediatric asthma
Dr. Goldblum's research focuses on the effects of environmental factors on the immunologic processes that underly the allergic respiratory diseases, especially asthma. The prevalence of these diseases is increasing in developed countries, with up to 30% of the population affected. In our region, an estimated 8-10% of children have been diagnosed with asthma. Since the most dramatic increases in asthma have occurred in industrialized countries, a causative role for environmental pollutants has been suggested. Recent novel observations by Dr. Goldblum's group suggest that the expression of some pollen allergens is enhanced by environmental stresses on the pollinating plants. Thus, allergenicity of the pollen from plants grown in polluted environments may be increased, leading to more allergic sensitization and symptoms. To test this hypothesis, he is leading a study to determine the effects of environmental factors, including ozone and UV light, on the expression of a pathogenesis-related protein, Jun a3, of the mountain cedar trees, a major source of seasonal allergic disease in several regions of the world. In order to better understand the structural requirement for proteins to serve as allergens, Dr. Goldblum is also collaborating with a group of investigators, including allergist and molecular biologists (Midoro-Horiuti) structural biologists (Czerwinski, Braun and Schein) and cellular immunologists (Brooks) to define the atomic features of allergens and their importance in the allergic response. These studies include molecular modeling and X-ray crystallography of cedar allergens; immunochemical mapping of epitopes and cellular models of the interaction of the allergens, specific IgE antibodies and mast cells. By comparing the molecular structures of closely and more distantly related allergen, they hope to define critical features of allergens that can be used to develop vaccines that will prevent common allergic reactions, including asthma. This collaboration recently achieved a major goal the resolution of the crystal structure of allergen Jun a 1 which as was published this year in the Journal of Biological Chemistry. As Director of the Child Health Research Center (CHRC) at UTMB, Dr Goldblum has been able to develop an academic, scientific environment in which students at all level of training (high school to junior faculty in Pediatrics) can perform state-of-the-art research under the mentorship of highly committed and productive senior scientists.
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.
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.
Professor and Interim Chair, Department of Human Biological Chemistry & Genetics
neuropathology associated with perinatal ischemic incidents typically associated with low birth weight infants due to environmental effects.
Our long-term goals are to understand the mechanisms of neuronal cell death and deficits associated with both acute and chronic trauma to the central nervous system at a molecular and cellular level. We have developed an array of interventions ranging from modified liposomal gene transfer, endogenous receptor antagonists and gene specific "decoy" inhibition of transcription factor binding to promoter sites as intervention approaches to therapy at the transcriptional level. We are also focusing on the role of intracellular trafficking in stress response mechanisms. Our hypothesis is that oxidative stress in the nervous system, caused by chronic or acute trauma, triggers inflammatory responses that result in the uncoupling of gene networks responsible for cell viability and function that result in the altered phenotypes associated with neural deficits present after injury. In addition, we hypothesize that trauma-induced phosphorylation events affect organelle occupancy by proteins regulating cell death. For example, inflammatory cascades activated by trauma have genotoxic and energetic consequences that activate stress response genes via the NF-B transcription factor. Transcription factors bind to cognate DNA sequences that regulate stress response gene expression essential to survival and function. We believe that transcription factor binding to cognate DNA sequences is finely tuned by the specificity of the sequence, position within a promoter and protein-protein interactions with other sites on a promoter. Our ongoing studies focus on: the Bcl-protein family of genes, COX-2, iNOS, and the IL-1 cytokine. We rely on in vitro and working animal models for perinatal ischemia, spinal cord injury, and head injury in rats and mice. In vitro models used are the PC12 line and primary cultures derived from fetal and neonatal brain. We use in vivo MRI techniques to assess damage and vascular changes in brain and spinal cord in addition to confocal immunocytochemistry to assess organelle function in response to oxidative stress. In vitro reporter constructs and transgenic models suitable to unraveling the role of the NF-kB transcription factor in transcriptional regulation of select genes are also used. In addition, we are applying genomic, proteomic and bioinformatics approaches to analyses of time course studies of post-traumatic injury response. Our animal studies look at outcomes to trauma and therapeutic molecular interventions in terms of locomotor functional recovery, cognitive and sensory outcomes. Studies are presently supported in part by NICHD, DOD, Israel/US Bilateral Agreement, Shriners and the Mission Connect Consortium. Collaborative efforts include the Baylor College of Medicine, University of Texas Houston Medical School, University of Leipzig, Germany, University of Montpellier, France, and Ben-Gurion University, Israel. We presently have two graduate students and two research associates and a visiting scientist in the group.
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.
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.
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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.
Professor, Department of Neuroscience and Cell Biology
Relevancy of rapid nongenomic actions of steroids to different types of cellular functions and to actions on hormone-responsive cancer cells.
Dr. Watson's research involves the identification and characterization of membrane forms of steroid receptors (for estrogens, xenoestrogens, progestins and glucocorticoids) and the signaling and functional responses mediated by them. Potent but imperfect signaling actions are initiated by estrogenic mimetics such as environmental and dietary estrogens. Membrane estrogen receptors are expressed on many types of normal and cancer cells. The Watson lab studies their involvement in growth control, peptide secretion, behavior, immune system function, and therapeutic apoptotic responses in cancer cells. The patterns of membrane steroid receptor regulation are different from their nuclear receptor counterparts and therefore may provide unique opportunities for therapeutic or remediation interventions. Liganding of these receptors cause rapid, nongenomic, signaling cascades including rapid release of prolactin, changes in cell attachment, calcium levels, cAMP levels, dopamine and serotonin transport, and MAP kinase (ERK, JNK, and p38), other kinase, and caspase activations.
Faculty Trainer in the UTMB Toxicology Training Program, and winner of the 2010 Teaching Excellence Award by the UTMB Graduate School of Biomedical Sciences.