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Currently Dr. Beamer is using both computer modeling and laboratory techniques in her research. She has developed an exposure and dose model that she is utilizing to estimate pesticide exposures of farmworkers’ children. As an expert in micro-activity patterns she is examining the activity patterns of older children and utilizing them to estimate dust ingestion. Dr. Beamer is also using GIS techniques to assess the risk of wheezing from exposure to traffic pollutants in early childhood. Dr. Beamer has built a laboratory to characterize exposure and risk of water-borne contaminants. Currently she is using this laboratory to measure the concentration of tricholoethylene in breastmilk and water contaminants in Nogales. She is conducting a field study to characterize how outdoor soil contaminants contribute to contaminant levels inside homes, of particular concern for communities near abandoned mines and hazardous waste sites.
We use unique primary tissue culture models of lung epithelial cells to study the cellular and tissue function of the lung epithelium. The conducting airway epithelium is an active cellular layer made up of a variety of cell types that is typified by ciliated airway epithelial cells that contribute to mucociliary clearance. The epithelial layer that lines the alveoli of the distal mammalian lung is made up of two distinct cell types, alveolar type I (AT1) and alveolar type II (AT2) cells. Physiological functions of AT1 cells include the primary site of gas exchange and of AT2 cells include the production of critical secretions that keep the lung from collapsing. Just as importantly, AT2 cells serve as "stem cells" that divide, migrate and differentiate to reform the AT1/AT2 epithelial layer following insult or injury. Also important to studies in our laboratory, lung epithelial cells provide innate immune function via a variety of events. These events include: the establishment of an epithelial "barrier;" the secretion of anti-microbial and inflammatory effector molecules; and direct interaction with non-epithelial cells (e.g. alveolar macrophages) to further immune function.Our current studies include three foci: 1) Host/Pathogen Interactions in the Airway; 2) Intercellular Communication in the Airway Epithelium; and 3) Re-establishment of a Functional Airway Epithelium following insult or injury. In the host/pathogen interaction studies, we are using a ciliated cell culture model to better understand early events in airway infection by primary colonizing bacteria from the Bordetellae. This includes elucidation of bacteria and host proteins that contribute to ciliary binding and the innate host defenses activated by this early host/pathogen interaction. In the intercellular communication studies we are elucidating the molecular mechanisms that allow for second messenger signaling within and between airway epithelial cells in the conducting airway and in the alveoli. In the epithelial repair foci, we are studying the contributions of extracellular matrix molecules and neighboring cells to the re-establishment of a functional airway epithelium following large-scale wounding or local disruption by toxicants and/or toxins.
Dr. Burgess has a broad research program working with multiple occupational and environmental populations. His occupational research projects are focused on reducing toxic exposures and preventing injuries among miners, firefighters and other first responders. His environmental focus has been on evaluation of population-level exposures to arsenic in drinking water and diet and improvement of emergency preparedness. He also heads training programs in industrial hygiene and mining health and safety, and is the Principal Investigator for the Mountain West Preparedness and Emergency Response Learning Center, which helps public health professionals and communities be better prepared for disasters of all types.
The effects of chronic arsenic exposure on protein quality control and how this relates to disease development and progression; development of methods to discover modulators of enzymes that are challenging to drug or proteins that are not enzymes.
Airway epithelial differentiation and mucous cell metaplasia in chronic airway diseases
Mucous cell metaplasia and mucus over-production are hallmarks of almost all chronic airway diseases (e.g. asthma, chronic obstructive pulmonary diseases, cystic fibrosis, etc.) and significantly increase the morbidity and mortality. No therapy is available besides the mechanical suction. We are now investigating the function and regulation of mucin genes in asthma pathogenesis using both in vivo (gene targeting model, induced mouse model of asthma, as well as tissues and secretions from asthmatic patients) and in vitro (differentiated epithelial culture and cell line) models.
A new paradigm in virus-induced asthma exacerbation
Airway rhinovirus (RV) infection is the major cause of asthma exacerbation, a severe precipitation of the symptom in otherwise stable asthmatics who are often still under the routine medication. Thus, asthma exacerbation may have a different pathogenic mechanism that is largely unknown at present. Among different asthma-inducing allergens, Alternaria (Alt) is a fungal species that causes asthma in arid and semi-arid areas. In collaboration with the researchers in Arizona Respiratory Center, we have found the shift of airway response to viral infection during Alt exposure, which promotes inflammation and depresses antiviral response. This shift causes further increase of viral production and inflammation, similar to what would happen in the airways of asthma exacerbation. We are currently investigating the potential underlying mechanisms using both in vivo and in vitro models.
Current research interests include studying molecular mechanisms of liver toxicity and employing a functional genomics approach based on flexible small-scale arrays to measure the expression of xenobiotic transporter and drug metabolism genes.
Specifically, thousands of people suffer from liver diseases such as biliary cirrhosis, steatosis, hepatitis or what is commonly referred to as chronic liver failure. During the early stages of these diseases, the normal functions of the liver slow down. Normally, the liver metabolizes toxic compounds and excretes them into the feces. However, in diseased patients, these toxic compounds can’t be eliminated fast enough and begin to accumulate in the liver and cause considerable toxicity. This in turn compounds the original condition leading to a progression of the disease and eventually liver failure.
Hepatic transporters are the driving force behind the excretion of these toxic substances and when turned off, cause the accumulation and toxicity associated with liver disease. However, a separate small group of transporters may be used to move toxic compounds from the liver, back into the blood (to be excreted in urine), thereby decreasing the exposure and toxicity to the liver. If the precise mechanism for the regulation of these transporters can be determined, new drug therapies that could artificially increase the capacity of diseased livers to excrete toxic substances and reduce liver failure would be possible. For this reason, pharmacologic intervention by targeting these new molecular pathways to relieve toxicity may prove to be vitally important to the long-term health of thousands of patients.
Dr. Karletta Chief is an Assistant Professor and Assistant Specialist in the Department of Soil, Water, and Environmental Sciences at the University of Arizona in Tucson, AZ. As an assistant professor, the goal of her research is to improve our understanding, tools, and predictions of watershed hydrology, unsaturated flow in arid environments, and how natural and human disturbances affect soil hydrology through the use of physically based methods. Dr. Chief research also focuses on how indigenous communities will be affected by climate change and collaborated in an interdisciplinary group of scientists including hydrologists, system dynamic modelers, and social scientists to determine how hydrological models can be improved to identify and mitigate risks to these vulnerable populations (nativeadaptation.arizona.edu). As an extension specialist, she works to bring relevant science to Native American communities in a culturally sensitive manner by providing hydrology expertise, transferring knowledge, assessing information needs, and developing applied science projects.
Molecular and genetic epidemiology of asthma and COPD
My lab is interested in understanding the mechanisms that work to create susceptible (and resistant) individuals within populations that are exposed to environmental toxicants. Much of our work focuses on arsenic, a metalloid toxicant commonly found in drinking water, air, and food in Arizona as well as around the world.Some of our work happens in real-world human populations exposed to arsenic. Our work has identified genetic variations and non genetic factors in arsenic-exposed people that identify individuals who will metabolize arsenic (chemically change the arsenic using enzymes in the liver) in a way that is associated with lower disease risk. We have found that genetic variants in a gene called AS3MT, as well as being overweight, result in this "safer" type of arsenic metabolism.In the laboratory we use lymphoblastoid cell lines, cell lines that we can grow in culture, made from hundreds of donors to generate "human populations" on the lab bench that we can test for variable response to toxicants like arsenic. Recent work by Alicia Bolt, a Pharm/Tox grad student currently supported by an IGERT fellowship, has identified a new cellular response called autophagy that is caused by arsenic exposure in these lymphoblastoid cell lines. We are excited because there is substantial person to person variability in the extent of autophagy induced by arsenic. We are using genomic techniques (genome-wide expression analysis) to try to understand why lymphoblastoid cell lines from some individuals are more susceptible to this toxic effect of arsenic.
Dr. Ledford¹s current work in the area of pulmonary surfactant
immunobiology combines her knowledge of mouse genetics, pulmonary disease
models and immune function regulation and focuses on understanding the
role of Surfactant Protein-A (SP-A) and how it regulates signaling
pathways within various immune cell populations. Specifically, she is
interested in how SP-A regulates degranulation, either directly or
indirectly, of two important cell types in asthma: mast cells and
eosinophils. More recently, Dr. Ledford¹s research has focused on
understanding how genetic variation within human SP-A2 alters
functionality of the protein in relation to eosinophil activities and how
this translates to characteristics observed in human asthma.
Projects include: 1. Water Talks! Risk and Safety Communication Research Program
2. Indigenous Voices -- Tribal Environmental Health Literacy Program
3. Summer Youth Environment Public Health Activities
4. Indigenous Voices Magazine Creation
Interns are not expected to have specialized skills. Useful skills to all projects are the desire to try something new, willingness to seek the application of environmental public health to a variety of other public health programs, and use of Microsoft and Adobe software.
My research interests lie in two principle focal areas. The first area is concerned with the microbial ecology and recovery of disturbed and marginal terrestrial ecosystems that are characterized by oligotrophy or nutrient poor conditions. Mine wastes, for example, occupy vast areas of the southwestern landscape and remain largely unvegetated for many decades. One constraint to natural revegetation of these wastes is nutrient poor conditions and the absence of healthy, plant sustaining microbial populations. Vital microbial communities must support nutrient generating activities such as nitrogen and carbon cycling and phosphate solubilization. We seek to understand patterns in microbial diversity that correlate with the sustainability of vegetation in disturbed regions and arid desert ecosystems. Both culture-based and molecular/phylogenetic-based approaches are used including metagenomic analysis of ecosystem communities.
The second focal area is the study of “eco-friendly” microbial surfactants (biosurfactants) including discovery of new biosurfactants, elucidating the microbial physiology associated with biosurfactant production as well as the role of biosurfactants in microbial survival. We also focus on the development of potential biomedical and environmental applications for these fascinating molecules. A current project evaluates the potential use of the biosurfactant, rhamnolipid, for harvesting key metals from industrial waste streams.
Pre-clinical stroke research to understand the role of sex differences and menopause in neuro-inflammatory mechanisms of brain injury during ischemic stroke.
Environmental research including health response to environmental exposures such as human exposure to metals, pesticides, volatile organic compounds, climate change, health, pollen and mold.
Dr. Piegorsch studies modeling and analysis for environmental data, with emphasis on environmental hazards and risk assessment. He coordinates these interests with his research in environmental toxicology, emphasizing mutagenesis and genotoxicology; geo-spatially referenced disaster informatics; multiple comparisons; and the historical development of statistical thought as prompted by problems in the biological and environmental sciences. He currently leads a research team developing statistical methods for estimating benchmark dose markers from environmental hazard analyses, for use in quantitative risk assessment. This research is funded by the U.S. National Cancer Institute and the U.S. EPA. He also has constructed statistical models for data from transgenic bio-technologies, developed guidelines for the design of bioassays in select transgenic animal systems, and has proposed retrospective designs for analyzing gene-environment and gene-nutrient interactions in human population studies.
Dr. Rainie studies the links between governance, health care, the environment and community wellness. She collaborates with a community of tribal leaders and program staff, researchers, and students at the UA's Native Nations Institute and Center for Indigenous Environmental Health Research , and elsewhere. She mentors numerous staff and students in responsible research practices, research administration, and leadership among other topics.
Dr. Ramos is recognized as a leading expert in the study of gene-gene and gene-environment interactions and genomic medicine. His research program integrates diverse approaches, ranging from molecular genetics to population-based public health studies in efforts to understand the genetic and genomic basis of human disease and to advance the goals of precision medicine. Ongoing basic science studies in his laboratory focus on repetitive genetic elements in the mammalian genome and their role in genome plasticity and disease, while his clinical work focuses on the characterization of diagnostic and prognostic biomarkers for chronic disease and cancer.
In the heart, cells that form the valves are induced to develop by interaction between endothelial cells and adjacent muscle. As a result, cardiac endothelial cells transform into mesenchyme and become the constituents of the valves and walls of the heart. This process is known as an epithelial-mesenchymal transition or EMT. The objective of my research program is to understand the molecular mechanisms that mediate cell transformation in the heart.Using a tissue culture assay, we showed that cardiac endothelia would only transform after stimulation by adjacent muscle. My laboratory has continued to examine the events which take place during this epithelial-mesenchymal cell transformation. Our studies focus upon three basic questions. 1) What is the nature of the signal produced by the muscle? 2) How do the target cells recognize the signal? 3) What events occur in the target cells in response to the stimulus? Answers to these questions will identify potential causes of congenital heart defects.Work in the laboratory initially focused on the observation that the growth factor, Transforming Growth Factor Beta, is a component of the transformation process. As this growth factor is actually a member of a family of related molecules, we used RNase protection assays to show that two isoforms, TGFbeta2 and TGFbeta3, were found in the heart. Experiments using antisense DNA oligonucleotides demonstrated that TGFbeta3 is the critical component. More recently, our work shows that both isoforms are used in complementary roles. Experiments show that this EMT in the heart is blocked by loss of several different classes of TGFbeta receptors, including Alk2, Alk5, TGFbetaType II, TGFbetaType III and Endoglin. As seen with the two different TGFbeta isoforms, each receptor component appears to mediate play a distinct role in the EMT process. Other experiments in this laboratory showed that EMT is sensitive to inhibitors of several classes of kinases, Gi proteins, and the phosphoinositide pathway. These pathways are being explored by cloning and targeted degradation of mRNAs of various components in order to track signals from the cell surface to the nucleus.Another approach to the problem is towards the identification of regulatory genes expressed in response to the cardiac signal. Our focus is the immediate early genes which are likely to be transcriptional regulators of other genes required for valve formation. Our most recent efforts have focused on the genes Slug (Snail2), Meox-1, Runx2 and Paraxis. All of these genes appear to be critical transcription factors for the process of cell transformation.A related research program in the lab is focused upon examining the relationship between events which take place during early valve development and the apparent cardio-teratogenicity of the environmental contaminant Trichloroethylene (TCE). In association with members of the Southwestern Environmental Health Sciences Center and the Superfund Program here at Arizona, we are trying to identify genes that are altered in developing hearts by exposure to this chemical.
Our research team focuses on the identification, fate, and environmental relevance of emerging chemical contaminants in the environment (http://snyderlab.arizona.edu/ ). We have developed rapid comprehensive chemical screening techniques using the latest generation of mass spectrometers and in vitro bioassays. In addition, we study the fate of chemical contaminants in the environment through natural and engineered treatment systems. Of particular interest is the identification and toxicity screening of transformation products that result from treatment processes, particularly oxidative technologies such as ozone, UV light, and chlorine. We also conduct toxicity identification and evaluation (TIE) techniques that use in vitro biological responses and subsequent high-resolution mass spectrometric analyses to identify and quantify toxic substances in complex environmental matrixes. As an example, our team has successful applied these methodologies to identify and mass-activity balance glucocorticoid steroids in the environment, resulting in the identification of potent endocrine disruptors which were previously not reported. We have also applied these techniques for drug discovery applications whereby we extract environmental samples, fractionate the extract, and expose the resulting fractions to in vivo and in vitro biological test systems in order to narrow the range of chemical substances responsible for immune response. At our newest facility, the Water & Energy Sustainable Technology (WEST) Center, we develop and apply demonstration-scale water purification technologies and evaluate the attenuation of emerging chemical contaminants and the formation of novel byproducts (http://west.arizona.edu/ ). Our team receives support from various governmental agencies as well as a diversity of private industries and non-government organizations focusing on water treatment and contaminant detection technologies.
The regulation of serine/threonine protein kinase pathways that function in stress-related signal transduction pathways is the research focus in my laboratory. To study these signal transduction pathways, molecular and biochemical approaches are utilized in order to understand the regulatory mechanisms that affect the activity of these kinases. These intracellular serine/threonine protein kinase pathways, which are referred to as mitogen-activated protein (MAP) kinase pathways, are activated by a number of hormones, growth factors, cytokines, and environmental agents. Currently, at least five MAP kinase pathways have been identified, and there are many protein kinases that function within a defined MAP pathway. One role for these sequential kinase pathways is to transmit an extracellular signal from the plasma membrane to the nucleus. Simply stated, these sequential protein kinase pathways provide the cell with an intracellular signal, which elicits a biological response that is appropriate for the type of stimulus. The cytoplasmic kinases that transmit the signal from the plasma membrane to various MAP kinase proteins include the MAP/Extracellular signal-regulated kinase (ERK) Kinase Kinase (MEKK) proteins. To date, at least four MEKK proteins have been identified based on a homology to similar protein kinases found in the budding yeast, Saccharomyces cerevisiae. However, the extracellular molecules that regulate the MEKK proteins remain largely undefined in mammalian cells. A major focus in my laboratory is to characterize the role of MEKK3 and MEKK4 in cellular signal transduction pathways. Current research focuses on the regulation of MEKK3 by the serine/threonine kinase, Akt, which functions in cell survival pathways and the inhibition of apoptosis. In another project we are characterizing the regulation of MEKK4 in response to arsenic in human keratinocytes. Finally, we are also studying the role of the PITSLRE protein kinase in the regulation of tyrosine hydroxylase, as it relates to nicotine signal transduction.
The central theme of the Functional Genomics laboratory is the characterization of the mechanisms through which natural variation in immune genes contributes to the pathogenesis of complex diseases, with special emphasis on respiratory disorders such as allergic inflammation and asthma. The approach taken is to assess the impact of genetic polymorphisms on the function and regulation of specific genes, focusing on those shown to be strongly associated with allergic inflammation and asthma phenotypes. Genes currently under study are IL13, GATA3, TLR2 and CD14. The laboratory evaluates how coding region polymorphisms result in the expression of proteins with altered biological properties. Complementary studies test the effect of genetic variation on transcriptional regulation and mRNA stability. A combination of biochemical purification and functional analysis is used to identify transcription factors that bind differentially to polymorphic alleles. The laboratory is also investigating the basic epigenetic mechanisms that regulate gene expression and the elements involved in gene regulation. More recently, the laboratory initiated genome-wide analyses of DNA methylation and gene expression patterns in relation to specific environmental exposures and genotypes. This work, performed in collaboration with the Genomics Shared Service of the SWEHSC, relies on comprehensive genetic databases generated at the Arizona Respiratory Center by re-sequencing innate and adaptive immunity genes in a large panel of reference DNA samples of known ethnicity, as well as in populations of defined allergic disease phenotypes. The next stage of the work, currently in advanced state of development, involves the generation of BAC transgenic mice to model alternative haplotypes of the genes of interest and to study their expression and phenotypic correlates in vivo. The ultimate goal of the Functional Genomics Laboratory is to establish a new paradigm merging analysis of genetic and environmental determinants of disease, and functional studies and patient phenotypes to understand the causes of disease and predict responsiveness to specific treatments.
Dr. Yoon directs Biosensors Lab (http://biosensors.abe.arizona.edu), who develops point-of-care diagnostic devices for various applications. Food-, water- and airborne pathogens have successfully been detected with