Department of Environmental and Occupational Health faculty members primarily focus their research efforts on respiratory and cardiovascular toxicology, free radical biochemical toxicology, computational and risk assessment approaches to environmental health, and molecular mechanisms of genomic instability associated with cancer and aging.
Our laboratory has focused on understanding both the subtypes of human asthma and the combination of environmental and genetic factors which drive them. Research has focused on the role of airway epithelial cells in human disease, given the position of these cells to link the environment with the host. Work encompasses use of large epidemiologic/research databases, including those both local and national, to define patient characteristics and relationships to environmental triggers, but also to include studies of specific human immunology, both in human samples and model systems. Current pathways of interest include those related to environmental and innate lung oxidative stress, as well as their intersections with inflammation, mucins and cell death pathways.
My laboratory efforts are directed toward original studies on the molecular and cellular biology of the lung. To date, this work has focused primarily on the role of oxidants and nitric oxide in affecting pulmonary endothelial and vascular smooth muscle cell function. Isolated primary cell cultures, genetically modified murine models, and somatic gene transfer to lung have been used as model systems to identify the role of partially reduced oxygen and nitrogen species in the response of the lung to stress and injury.
The primary focus of current research is investigating the cellular and molecular mechanisms underlying human blood vessel and lung diseases caused by environmental exposures to metals and chronic changes in redox status. In vivo and cell cultured-based studies focus on the molecular pathology and etiology of vascular disease caused by chronic exposure to low levels of arsenic in drinking water. The cell signaling pathways that mediate arsenic stimulated pathogenic phenotypic changes in endothelial cells are being investigated. Additional studies examine the molecular signaling mechanisms mediating gene induction and silencing in airway epithelial cells exposed to chromium. The objective of these studies is to identify the pathways through which inhaled chromium aggravates lung injury from infections and exposure to other metals.
Currently, we are working in the area of cellular signaling mechanisms of lung injury with emphasis on acute lung injury induced by particulate air pollutants such as nickel. In particular, we will investigate the role of TGF a- and TGF b-regulated signaling pathways in nickel-induced acute lung injury. Molecular and tissue culture-based studies will focus on identification and characterization of key signaling proteins, transcription factors, and promoter sequences that modulate susceptibility to nickel-induced acute lung injury. These studies, combined with animal studies, will advance our understanding of the genetic determinants of acute lung injury.
Our laboratory is interested in investigating effects of environmental stress such as toxic chemicals and microorganisms on airway epithelial cell differentiation and lung diseases. One of our current research projects is focused on elucidating the molecular mechanisms that regulate the interaction between airway epithelial cells and exposure to environmental insults such as TCDD and tobacco smoke. We are also interested in how environmental agents affect host defense mechanism, especially airway secretion and infection that relates to pulmonary disease. The ultimate goal of our laboratory is to develop new potential biomarkers for early detection of preneoplastic lesions that is caused by environmental exposure, as well as for the development of novel treatment strategies against toxicant-induced respiratory pathogenesis.
My overall research mission is dedicated to the investigation of cellular mechanisms by which various environmental agents, particularly those that affect the lung, perturb cell physiology, and, thus, contribute to organ dysfunction during toxicity. Only by understanding the cellular and molecular mechanisms of toxin action can effective chemopreventive and therapeutic strategies be designed. Of primary current interest is the role of oxidative stress, not only as a mediator of cellular damage, but also as a physiologic signaling mechanism that can dictate numerous cellular responses.
Kagan’s laboratory and Center for Free Radical and Antioxidant Health has been studying redox mechanisms of physiological processes in cells and tissues as well as their aberrant changes caused by exposure to environmental factors and disease conditions. The major focus of this work is on phospholipids and their role in signaling. The Lab has developed highly sensitive and specific LC-MS based protocols for the detection, identification and quantitative analysis of oxidatively modified lipids. With this technological advancement, the major efforts are directed towards understanding and deciphering the signaling language of peroxidized phospholipids. Among the most advanced areas of research are studies of phospholipid signals in programs of regulated death such as apoptosis, necroptosis and ferroptosis. This work resulted in the discovery of new mechanisms of cell death in acute brain injury, acute radiation syndrome, pulmonary diseases (including ARDS, asthma and bacterial pathogen/host interactions in the lung), organ transplantation. Another aspect of the current work is related to decoding of mechanisms of lipid reprogramming of innate immune cells in tumor microenvironment leading to immunosuppression of myeloid cells in cancer. Unearthing of new enzymatic mechanisms of redox phospholipid signaling leads to the design and development of new therapeutic modalities. This work is also going on in the Lab.
My research focuses on understanding the molecular mechanisms of mutagenesis and the mutational pathways that link environmental chemicals to cancer. We have developed and applied new molecular approaches to determine the mutational spectra for potential carcinogens. Thus, our studies include identification of the types, positions, and frequencies of mutations after treatment with the chemical agent.
Our laboratory uses broad approaches to dissect regulatory networks and to explore the role of lipid-associated genes and proteins in molecular pathogenesis of Alzheimer’s disease.
Current projects relate to genetically modified mouse models of Alzheimer’s disease (AD) and cholesterol metabolism. A particular focus is on liver X receptors (LXR). Their regulatory function in the brain in health and disease is being approached using complex transgenic mouse models of altered lipid metabolism. Behavioral phenotyping and histopathology are used to reveal clues of LXR-controlled regulatory networks in the brain. Age-dependent and disease-related changes in immediate early genes (IEG) response to environmental factors is the second major research theme. Molecular, pharmacological, and genetic approaches; gene profiling; and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) in intact animal models of AD are being used to assess IEG-controlled signaling pathways. AD pathogenesis in those models is assessed in the context of gene-environment interactions genome-wide using high-throughput genomic and epigenetic tools, diet, and dietary manipulations.
I am investigating the functional genomics of acute lung injury, asthma, and chronic obstructive pulmonary disease. Molecular mechanisms by which air pollutants exacerbate or cause lung diseases are being studied by various strategies including genetic linkage and microarray analyses and transgenic/gene-targeted murine systems. A major research interest is uncovering the genetic basis of increased susceptibility to pulmonary epithelial injury and repair. In addition, recent studies are examining transcriptional regulation of molecular targets (e.g., surfactant proteins) altered by exposure to ozone, aldehydes, and particulate matter.
I am studying molecular mechanisms of genomic instability associated with cancer and aging with an initial focus on telomeric DNA, genetic and environmental factors that alter rates of telomere attrition, mechanisms of telomere loss in the progeroid disorder Werner syndrome, roles of the Werner syndrome protein in repair and replication of telomeric DNA, and cellular pathways that repair and restore damaged telomeric DNA.
***Dr. Opresko is the 2020 recipient of the Merrill J. Egorin Excellence in Scientific Leadership Award. This award honors a faculty member that exemplifies scientific passion and scholastic dedication.***
My focus is the study of mechanisms of lung injury and repair in response to particles and the biology of bone marrow-derived Mesenchymal stem cells and their use during lung injury and repair.
I am conducting studies of the interactions of reactive oxygen, nitrogen, and radiation with mitochondria, particularly using microelectrodes and magnetic circular dichroism spectroscopy.
My research focuses on (1) amelioration of acute cyanide toxicity, (2) the cytotoxic effects of nitric-oxide-derived oxidants, (3) ionizing radiation-induced mechanisms of cell death, and (4) application of magneto-optical spectroscopy to the study of biological systems.
My current research focuses on deciphering how environmental pollutants/allergen and dietary factors alter the epigenome via DNA de/methylation and induce chromatin remodeling, leading to complex diseases like asthma, cardiovascular diseases, sleep apnea and cancer. My long-term goal is to apply innovative and promising epigenetic approaches to understand the underlying mechanisms by which epigenetic changes may contribute to common diseases. Our findings may lead to the development of improved preventive measures and therapeutic strategies to reduce the burden of chronic diseases. Also, translating our scientific findings into human may provide proper disease management and lifetime recommendations to the public.
My goal is to elucidate the molecular mechanisms through which lipid metabolites regulate cellular membrane structures as well as membrane-bound complexes, particularly under conditions of oxidative/nitrosative stress.
My primary research is concerned with the role of free radical reactions and, more specifically, the role of lipid peroxidation in apoptosis.
My research has been focused on airway epithelium physiology and cell biology in respiratory disease, particularly the role of Th2/15LO1/autophagy/ferroptosis as related to asthma pathogenesis. 15-Lipoxygenase 1 (15LO1) is one of the several key enzymes in arachidonic acid (AA) metabolism. We were the first to identify that 15LO1 competes with and displaces Raf-1 from its binding with Phosphatidylethanolamine-binding protein 1 (PEBP1), which plays a critical role in asthma pathogenesis. Our ultimate goal is to identify the modification of 15LO1/PEBP1 interaction as a novel therapeutic approach to dampen inflammatory processes in asthma and other diseases.