Research is aimed at evaluating genetic and epigenetic mechanisms in environmental chemical carcinogenesis. Specific project areas are concerned with toxicity assessments of conazole pesticides, arsenic, and water
disinfection by-products. Human and rodent cells are analyzed for chemical-induced alterations in DNA
methylation and gene expression in combination with chromosome damage, cell toxicity and histopathological
effects. Ultimate goals are to improve the scientific basis of risk assessment, and include evaluations of lifestage
and nutritional susceptibility risk factors which may modulate chemical toxic/carcinogenic effects.
My research focuses on developing biologically based models for the uptake, distribution, metabolism, and biological effects of drugs and chemicals and their application to safety assessments and quantitative health risk assessments. In recent years, my research emphasis has been on developing mathematical descriptions of control of genetic circuitry and the dose-response and risk-assessment implications of these control processes.
Metabolism and disposition of xenobiotics in vivo and in vitro: isolation, identification, characterisation and quantitation of radioactive and unlabelled metabolites and DNA adducts. Enzymology of mixed-function-oxidase-dependent reactions. Toxicology of food additives, contaminants and environmental pollutants. Genotoxicity, mutagenicity and DNA binding of polycyclic aromatic hydrocarbons and nitrosubstituted arenes, and of water disinfection products.
Research in the Brouwer laboratory is focused on: (1) hepatobiliary xenobiotic disposition, including mechanisms of hepatic uptake, translocation and biliary excretion; (2) development/refinement of in vitro model systems to predict in vivo hepatobiliary disposition, drug interactions, and hepatotoxicity; (3) hepatic drug transport; and (4) pharmacokinetics, including aberrant gastrointestinal drug absorption phenomena.
The Cancer Biology Group at NIEHS focuses on early events in skin tumor development using a transgenic mouse model (TgAC). This model possesses a v-Ha-ras transgene under the regulation of a fetal globin promotor integrated at an ectopic site which confers a unique phenotype of inducible skin papillomas with a high rate of progression to invasive squamous and spindle cell neoplasms. The goals of our studies are to identify and characterize: 1) The cellular origin of the tumors and 2) critical genes which are involved in ras-mediated tumor induction and progression. Conventional cancer therapies have until recently depended on treatment late stages of tumor growth and involved non-specific mechanisms of cellular injury. By focusing on understanding early events in tumor induction we hope to gain insights into targets for intervention that can more specifically inhibit cancer cell growth.
Steroid hormones regulate tissue-specific gene expression in animals via receptor dependent intracellular signal transduction pathways. We are particularly interested in glucocorticoid receptors and their actions on the immune system because they reflect the primary response to environmental stress. Current research projects are examining the following aspects of glucocorticoid hormone action. A second major interest of the laboratory focuses on evaluating the mechanisms involved in the regulation of apoptosis in normal and neoplastic cells. Research is aimed at the identification and cloning of genes that are responsible for both the initiation and execution of apoptosis.
Diabetes and insulin resistance: lipid and carbohydrate metabolism; obesity: partition of energy between triacylglycerol storage and fatty acid oxidation; regulation of triacylglycerol synthesis; hepatic steatosis
Mechanisms of DNA replication, DNA repair, and cell cycle checkpoints are studied in cultured human cells and using biochemical assays in vitro. It includes translesion synthesis by DNA polymerase eta and its role in suppressing mutagenesis by solar radiation. Inherited and acquired defects in the network of protection of genetic stability are associated with increased risk for mutations underlying cancer pathogenesis. Current goals are to identify key molecular events in melanoma development associated with sun exposure. Other collaborative studies aim at localization of functional origins and characterization of DNA replication dynamics.
Dr Costa's primary research interests focus on the potential for air pollutants to adversely affect human health. By using animal models representing healthy and susceptible human populations (chronic heart and lung diseases), he has made major in-roads into understanding how contaminants in the air can cause illness and even death. He uses methods in cardiopulmonary and neuro-physiology coupled with modern cell-molecular biology to develop these models and to ascertain how health impairments influence responsiveness to pollutant stresses.
Our laboratory has research interests that include developmental neurotoxicity, with an emphasis on the use of mode-of-action models to study the impact of endocrine disruptors and the cumulative risk of thyroid disruptors and pesticides.
My interests focus on developing quantiative methods to assess the relationships between exposure, dose and response. This research has examined methods for dioxins, thyroid hormone disruptors and pyrethroid pesticides.
1) Identification of critical elements of human genetic variability contributing to pain sensitivity and pathophysiological pain states, 2) identification of therapeutic targets for pain management, 3) studying molecular hierarchy of functional SNPs commonly present in human population and 4) studying the molecular mechanisms of gene expression regulation.
Investigation of genes/proteins that play key roles during embryonic and postnatal development of craniofacial/oral/dental structures; and their contribution to normal variation and to congenital and acquired disorders.
Involvement of the epidermal growth factor receptor and its ligands in development, differentiation, and carcinogenesis of the mammary gland. Signaling mechanisms of endocrine disrupting toxicants having adverse effects on mammary gland development and the ability of the gland to lactate. Mechanism of action of atrazine, simazine, and cyanazine in the brain.
The Neurotoxicology Group examines the role of microglia interactions with neurons and the associated immune-mediated responses in brain development and aging as they relate to the initiation of brain damage, the progression of cell death, and subsequent repair/regenerative capabilities. We have an interest in the neuroimmune response with regards to neurodegenerative diseases such as, Alzheimer's disease.
Our research focuses on determining the mechanisms responsible for craniofacial birth defects. We use the whole embryo culture system to expose mouse conceptuses to toxicants and evaluate morphological, molecular (Affy arrays) and protein changes. Antisense morpholinos and adenoviruses are used to modulate gene expression and determine phenotypic effects. We are using embryonic stem cells as a model to evaluate the effects of environmental chemicals on differentiation. Using molecular markers to identify differentiation may provide critical information to identify developmental toxicants.
Research in my lab focuses on the mechanisms by which exposure to air pollutants can enhance the susceptibility to and the severity of respiratory virus infections. Specifically, we are examining the effects of air pollutants such as diesel exhaust and cigarette smoke on influenza virus infections, using several in vitro models of the respiratory epithelium. In
collaboration with physicians from the Department of Pediatrics, we are also translating these studies into humans in vivo.
Research in the Kaufmann laboratory is concerned with determining the mechanisms whereby cell cycle checkpoints suppress human cancer development. We are focused on two checkpoints that help to stabilize the genome. The decatenation G2 checkpoint delays mitosis until daughter chromatids are sufficiently disentangled by topoisomerase II. This checkpoint is regulated by the breast cancer susceptibility gene BRCA1. The intra-S checkpoint regulates DNA synthesis by controlling the rates of replicon initiation and DNA chain elongation. This checkpoint is regulated by two proteins, Timeless and Tipin, that mediate signaling at stalled replication forks. A program project is studying how the Timeless-Tipin replication fork protection complex protects against UV-induced chromosomal damage and sunlight-induced melanoma.
Dr. Macdonald is the Founder and Scientific Director of the new Metabolomic Facility and Co-Scientific Director of the joint UNC/NCSU/NOAA Marine MRI facility at Pivers Island near Beaufort NC. Dr. Macdonald's research goal is to combine metabolomics and tissue engineering and apply these tools to quantitative biosystem analysis.
Research description: Exposure to ambient air particulate matter(PM) has been associated with increased human deaths and cardiopulmonary morbidity, such as lung infections and increased asthma symptoms. I am investigating some types of PM and associated gases (such as aldehydes) that may be associated with those health effects so that the US EPA may be able to better regulate or manage the sources of the PM which are identified as playing a role in the adverse health outcomes. I am currently focusing on the effects of diesel exhaust using a variety of approaches ranging from exposing cultured human cells to the exhaust, to studying responses of humans exposed out in traffic. The EPA rules for diesel exhaust from large trucks to be implemented in 2007 and 2010 will drastically change the type of emissions, and I am currently designing and implementing testing strategies to assess the toxicity of the future types of diesel emissions. Additionally some of my research effort attempts to identify what populations are more sensitive to the effects of air pollutants, and the genetic and environmental reasons behind the increased sensitivity.
Protein-derived radicals, in vivo detection of free radical generation, biomarkers of oxidative stress and free radical formation in aids-related infection (Pseudomonas aeruginosa)
Dr. Millikan's research interests include the role of genetics in human cancer, including the study of how inherited variation in DNA repair interacts with environmental factors in breast cancer, colon cancer, and malignant melanoma. He is also interested in carcinogen metabolism, and identifying causes of breast cancer in young women and African American women.
Function, expression and trafficking GABA-A receptors in the CNS; effects of chronic ethanol exposure that leads to ethanol tolerance and dependence; role of endogenous neurosteroids on ethanol action and adaptations; etiology of essential tremor.
My research interests include the endocrinology of pregnancy and parturition; reproductive and developmental toxicity testing; mixtures toxicology; structure-activity relationships; axial skeletal development; and strain differences in toxic responses.
My research focuses on understanding the relationship between dermal and inhalation exposure and the effect of individual genetic differences on the function of enzymes that detoxify hazardous agents and that affect the development of disease. My research group has pioneered approaches to quantitatively measure skin and inhalation exposures to toxicants; additionally, my group has developed sophisticated exposure modeling tools using mathematical and statistical principles in an effort to standardize and improve exposure and risk assessment.
Bioinformatics, Cancer Biology, Cell Biology, Chemical Biology, Computational Biology, Genomics, Molecular Medicine, Neurobiology, Pharmacology, Systems Biology, Toxicology, Translational Medicine
Our laboratory applies molecular, biochemical, genetic and genomics approaches to understanding the mechanisms of environmental agent-related organ injury and carcinogenesis. Specifically, we are interested in nuclear receptor-mediated pathways in chemical carcinogenesis, oxidative DNA damage and repair, the role that alcohol and diet play in cancer, and the genetic determinants of the susceptibility to toxicant-induced liver injury. Through a combination of in vivo animal studies and experiments that utilize cellular and molecular models, we aim to better understand why certain chemicals cause cancer or organ damage in rodents and whether humans in general, or any susceptible sub-population in particular, are at risk from similar exposures.
Research interests center around interactions between xenobiotic compounds (ambient and indoor air pollutants as well as food allergens) and the immune system and consequent effects on infectious and allergic disease. The laboratory has developed several rodents models of infetious and allergic disease. The focus is to understand the effects that exposure to environmental agents may have on both local and systemic immune responses, the underlying mechanisms associated with these effects, the consequent impact on susceptibility to disease, and the relationship between rodent data and human health effects.
The lab relies on murine genetic approaches to study the roles of the INK4/ARF tumor suppressor locus in human cancer and aging. At present, the lab has two main focuses:
Stem Cell Aging:
Cancer and degenerative diseases are much more common in old people than young. Although this has been well-recognized in clinical medicine for decades, scientists do not agree as to why this occurs. Recently, work from several labs including our own has shown that humans age, in part, because important regenerative cells lose their capacity to divide with the passage of time. That is, the tissues and organs from old people are less able to replace and regenerate lost or damaged cells than the corresponding tissues and organs from young people. Our lab has studied mechanisms that underlie this age-dependent failure of cell division; in fact, we have shown the surprising result that cellular programs that function to prevent cancer untowardly also calls aging. Specifically, cellular “senescence” is now believed to be of major importance in the process of aging. Senescence refers to a permanent growth arrest induced in formerly dividing cells by the activation of genes that prevent cancer. The good news in this system is that the normal functioning of these ‘tumor suppressor genes’ prevents cancer; the bad news is that these same genetic events appear to cause aging by activating cellular senescence.
Melanoma and Murine Models of Cancer:
Because of the important role of p16INK4a in preventing melanoma, the lab has long been interested in this particularly deadly form of skin cancer. Specifically, we are interested in using genetically engineered models of cancer to study melanoma genetics. We have shown a role for the p16INK4a-RB and ARF-p53 tumor suppressor pathways in repressing this important human cancer in response to RAS-RAF activation. We have generated highly faithful models of human melanoma, and have used these to study novel therapeutics. We have also discovered a novel human melanoma sub-type based on expression profiling, and have identified a new therapeutic target (CD200) for treatment of melanoma.
Dr. Smiths research interests are in correlating pharmacokinetics and metabolism of drugs with their pharmacodynamics and toxicity. Research efforts in this area include in vitro studies and in vivo animal experiments aimed at understanding mechanisms of processes that influence drug disposition and toxicity. Where possible, transitional studies in human subjects are conducted to demonstrate clinical relevance and the potential application to humans. A primary emphasis in the laboratory is the process of glucuronidation, the major Phase II metabolic pathway where the sugar, glucuronic acid, is coupled to drugs and other xenobiotics.
Research interests involve metabolic interactions of essential microelements, especially trace metals, with toxic metals and metalloids that contaminate food chain and drinking water reservoirs. Research topics include: the interactions between selenium, an essential micronutrient, and arsenic, an environmental contaminant and human carcinogen; the enzymes and co-factors involved in the metabolism of arsenic and selenium; the mechanisms of arsenic- induced diabetes; and, the role of nutritional antioxidants and antioxidant enzymes in responses to the oxidative stress induced by exposure to environmental toxins, by viral infections or nutritional deficiencies.
My laboratory focuses on understanding mechanisms of carcinogenesis, with emphasis on the role of DNA damage and repair. During the last few years, we have developed ultra-sensitive and highly specific mass spectrometry methods for measuring the DNA and hemoglobin adducts of vinyl chloride, crotonaldehyde, ethylene oxide, propylene oxide, styrene oxide, butadiene, malondialdehyde, cis-platin and O6-methyldeoxy-guanosine, as well as slotblot methods for AP sites and oxidative DNA damage. These methods have been applied to understanding critical mechanisms in carcinogenesis, as well as undertaking molecular epidemiology studies of workers in the butadiene and reinforced plastics industries. We are also examining changes in gene expression associated with oxidative stress and environmental chemical exposure.
The Cancer Biology Group at NIEHS focuses on early events in skin tumor development using a transgenic mouse model (TgAC). This model possesses a v-Ha-ras transgene under the regulation of a fetal globin promotor integrated at an ectopic site which confers a unique phenotype of inducible skin papillomas with a high rate of progression to invasive squamous and spindle cell neoplasms. The goals of our studies are to identify and characterize: 1) The cellular origin of the tumors and 2) critical genes which are involved in ras-mediated tumor induction and progression. Conventional cancer therapies have until recently depended on treatment late stages of tumor growth and involved non-specific mechanisms of cellular injury. By focusing on understanding early events in tumor induction we hope to gain insights into targets for intervention that can more specifically inhibit cancer cell growth.
Our laboratory uses the mouse as a model to study phenotypes with complex etiologies contributed by genetic and environmental factors and that underlie differences in susceptibility to common diseases. Genetics and a broad range of genomic, bioinformatic and computational tools are used in a new integrative field called systems genetics. Through many collaborative interactions, major research foci are currently in development, reproduction, neurobiology, cancer (colon and breast), cardiology, exposure biology and computational genetics. Our laboratory is also investigating the function role of the Egfr/Erbb gene family of receptor tyrosine kinases through embryonic stem cell manipulation, transgenics, gene targeting and other genetic engineering technologies.
The major area of our research is Biomolecular Informatics, which implies understanding relationships between molecular structures (organic or macromolecular) and their properties (activity or function). We are interested in building validated and predictive quantitative models that relate molecular structure and its biological function using statistical and machine learning approaches. We exploit these models to make verifiable predictions about putative function of untested molecules.
Our work focuses on molecular aspects of androgen receptor regulation of gene expression, which includes coactivator interactions with the androgen receptor and its functional importance in various clinical syndromes.
