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Record Count: 8
To sort columns alphabetically or numerically, click on the column
header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant): The hexavalent oxidation state of chromium, chromate or Cr(VI), is a known human carcinogen. Human exposure to this carcinogen occurs in chrome-utilizing occupations and from environmental sources that are primarily anthropogenic. Despite conservation and recycling efforts in the United States, over 20,000 metric tons of chromium is released to the environment every year with over 5000 metric tons as atmospheric emissions. The ubiquity of Cr(VI) emissions to the environment has led the ATSDR to list this metal as one of the top 20 high priority toxic agents for emission reduction. While Cr(VI) is well-established as a toxic DNA damaging agent, the mechanism(s) of DNA damage and the DNA lesions that are produced are still unknown. We have recently identified of several new "further oxidized" guanine lesions in DNA that arise from Cr(VI) treatment from both in vitro and cellular systems. These lesions have demonstrated many of the same biological effects in cell systems that are associated with pathologies of Cr-induced lung cancers. Based on these findings, we propose to test the hypothesis that "chromate exposure leads to the formation of a subset of further oxidized guanine lesions in DNA that are ultimately responsible for the cellular events that give rise to cancer". The approach that we will use to test this hypothesis will be; 1) We will test the selective toxicity of chromate towards a set of model, DNA-repair deficient, cell lines and determine the spectrum of oxidized lesions that arise, 2) we will determine how modulation of intracellular reduction potential may affect chromate sensitivity in these cell lines and determine whether this intracellular reductant modulation effects the relative lesion distribution, 3) we propose to identify the potential for oxidation of DNA by chromium to form DNA-reductant, DNA-amino acid and DNA-protein crosslinks, and 4) we propose to determine the effect that these crosslinks have on cellular function with regard to mutations, DNA repair and gene transcription. The end result of this study will be a fundamental insight into the process by which oxidative DNA damage caused by Cr(VI) forms lesions that impair critical cellular processes. This research will also serve to identify novel biomarkers of Cr(VI) exposure and suggest repair genes that can be analyzed for polymorphisms and mutations.
DESCRIPTION (provided by applicant): The Aryl hydrocarbon receptor (AhR) mediates the toxic effects of a broad class of environmental contaminants, the halogenated aromatic hydrocarbons. Moreover, the immune system is a very sensitive target of the prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD-induced immune dysfunction is characterized by profound suppression of T cell-mediated immunity and increased susceptibility to disease. Dendritic cells (DC) that function to induce the activation, expansion and differentiation of T cells are postulated to be direct targets of TCDD. DC aberrantly express critical costimulatory molecules and undergo premature deletion from immune tissues following AhR activation by TCDD. Therefore, we hypothesize AhR activation in DC causes defects in their activation and/or survival and ultimately contributes to the suppression of adaptive immunity. The focus of this laboratory is to understand the cellular and molecular basis for the potent immune suppression induced by AhR ligands, while the primary objective of this proposal is to determine the mechanisms underlying TCDD-induced suppression of DC functions. These objectives will be determined by the following four Specific Aims: (1) to define the role of AhR activation in the fate and function of DC; (2) to determine if the effects of AhR activation in DC are mediated exclusively via the Dioxin Response Element (ORE); and (3) to investigate the involvement of the Fas/Fas ligand pathway and cell cycle perturbation in AhR-mediated DC death. The research proposed in this application will have significant, positive effects on human health. This work will advance our basic understanding of DC interactions with antigen-specific T cells. It will define mechanisms of xenobiotic-induced immunotoxicity, and may identify novel therapeutic approaches to generate tolerogenic DC.
DESCRIPTION (provided by applicant): Although particulate matter (PM) exposures have been linked with poor respiratory health outcomes, most of these studies have focused on air sheds with urban and industrial sources of PM2.5. Wood smoke-derived PM also contributes to ambient PM in these urban areas, and is the major source of PM in many US rural or peri-urban areas, as well as in many communities within developing countries. This study will focus on indoor air quality and clinically relevant changes in health effects among asthmatics living in homes whose primary heating sources are non EPA-certified woodstoves. The Primary Aim of this study is to assess the efficacy of residential interventions to reduce indoor PM exposure from woodstoves and the corresponding improvements in quality of life and health outcomes for asthmatic children. The study area for this project will be three rural communities in Idaho and western Montana, including one Indian Reservation. This study will use a three arm (Tx1, Tx2, and Tx3) randomized placebo-controlled intervention trial. The interventions will be at the household level, and exposure and outcomes will be assessed for one asthmatic child in each household. Households in Tx1 will receive inactive high efficiency particulate air (HEPA) devices and will serve as the placebo group. Households in Tx2 will receive a new EPA-certified woodstove, while households in Tx3 will receive active HEPA devices. The Secondary Aims of this study are to assess the impact of these interventions on residential PM2.5 exposures and other health outcomes. Secondary exposure outcomes measured prior to and following the intervention will include PM2.5 mass, chemical wood smoke markers on PM2.5 filters (including levoglucosan and abietic acids), and biomarkers of wood smoke exposure in urine and exhaled breath condensate. Secondary asthma-related health outcomes measured prior to and following the intervention will include peak expiratory flow (PEF) and forced expiratory volume in first second (FEV1), biomarkers in exhaled breath condensate (i.e., pH and nitric oxide), and frequency of asthma symptoms, medication usage, and healthcare utilization. To our knowledge, this will be the first randomized trial in the US to utilize a wood smoke intervention to assess the impact of the consequent reductions in indoor PM on health outcomes in a susceptible population. The results from this project will be translatable to other regions in the US and the world where biomass burning is commonly used for heating and cooking. Relevance: This study will determine if reductions in PM2.5 from residential woodstoves, a common source of indoor air pollution, will result in health improvements among asthmatic children. Clinically significant health outcomes will be measured. Results from this study will provide important information for implementing public health strategies for asthma management in the presence of this common exposure.
DESCRIPTION (provided by applicant): Crystalline silica is well known to induce chronic lung inflammation that can progress to fibrosis, i.e. silicosis. Despite existing standards, silicosis remains a prevalent health problem in the United States and throughout the world. Because it is a known causative agent of lung fibrosis, it is often used to study mechanisms of fibrogenesis under controlled conditions in animal models. While much has been learned, there is still insufficient information on the molecular and cellular mechanisms leading to fibrosis to develop effective therapeutic approaches. It is generally accepted that alveolar macrophages are the initial cellular targets following silica inhalation and that macrophages are involved in the initiation of inflammatory signals and that mostly likely lymphocytes are also involved, since Th1- and Th2- associated cytokines have been repeatedly implicated in the process of fibrosis. Based on recent data from our laboratory, as well as others, implicating activated lung macrophages (aMQ) and NK lymphocytes as being sufficient to set off the inflammatory cycle leading to fibrosis we propose to test the central hypothesis that aMQ with NK lymphocytes constitute steps in the development of chronic inflammation progressing to silicosis. We will use the following three aims to test this hypothesis: Specific Aim 1: Characterize the silica-exposed alveolar macrophages that traffic to the interstitial spaces, acquire an immunostimulatory phenotype, and play an integral role in the generation of the aMQ. Specific Aim 2: Demonstrate that NK activation by the aMQ is sufficient to generate the inflammatory requirements for lung fibrosis. Specific Aim 3: Ascertain the nature and molecular components of the aMQ-NK interface that results in the generation of a pro-fibrotic environment. This proposal is novel in that it will address the complex interactions between aMQ and NK within the context of the respiratory system using both in vitro and in vivo models. Upon completion of these studies, we expect to establish and test the relative contributions of specific subpopulations of macrophages and NK cells and determine those candidate molecules and signaling pathways by which these cells communicate leading to chronic inflammation and fibrosis. Furthermore, this body of work is anticipated to generate knowledge that will direct the development of novel therapeutic targets for the management of respiratory illnesses, including silica-induced inflammation and fibrosis.
DESCRIPTION (provided by applicant)
This SBIR project is in response to the call for the development of field-deployable or wearable personal sensors for monitoring point-of-contact exposures to airborne chemicals through biosample testing. The broad objective of this proposal is to develop an extremely sensitive and selective biosensor device capable of detecting and discriminating proteins in human serum samples taken from patients suspected of being exposed to potentially harmful levels of organophosphate-based pesticides. This represents a novel approach in biomarker analysis because each organophosphate (OP) pesticide results in a distinct protein "fingerprint" structure that can be identified, distinguished from other agents and their conjugates, and quantified. Using ATERIS Technologies novel sensor thin polymer film technology, reporter domains will be customized with specific protein-recognition molecules that detect the OP poisoned proteins. This will make it possible to develop an inexpensive, yet highly rapid, sensitive, and accurate device to analyze exposure to OP pesticides, assess the type and extent of OP agent exposure and then this information will guide the therapeutic intervention necessary. The major milestones in this Phase I SBIR project are first to isolate biorecognition proteins capable of discriminating between native and OP-poisoned human proteins, then show proof-of-principal for the sensitivity and reliability of the film sensor element. In the Phase II of this program, the detection films will be incorporated into a reader device and the reproducibility and accuracy of detection of OP-modified proteins in actual serum samples will be determined. The data generated will guide the design of the commercial biosensor device. The end user of such a device will be the field personnel likely to be exposed to OP pesticides and clinical laboratories likely to encounter patients that are suspected to have been exposed to OP chemical agents.
DESCRIPTION (provided by applicant)
The Center for Environmental Health Sciences (CEHS) at The University of Montana has had an active high school and undergraduate training program to help prepare students for graduate training and a research career. Through a Science Education Partnership Award (SEPA) funded through the National Center for Research Resources (NCRR), CEHS has established a strong partnership with local high schools in environmental science education. The Short-Term Educational Experiences for Research (STEER) program will serve as a bridge between the SEPA goals and increasing the number of motivated students wanting to pursue a career in Environmental Health Science research. The overall goal of the STEER training plan is to provide a stimulating educational environment for high school and undergraduate students through a combination of didactic, group learning and hands-on basic research experiences that will encourage these students to pursue careers in Environmental Health Sciences (toxicology). This will be accomplished through the following aims: Aim 1: To provide an interactive educational experience through an entry level didactic course in toxicology combined with integrated group learning activities and group appropriate seminars; Aim 2: To provide training in bench research in Environmental Heath Sciences working in laboratories of successful investigators and their groups; Aim 3: To conduct objective evaluation of all aspects of the training program to effect continuous improvement and document success of the program; and Aim 4: To train a significant number of Native American students during the 5-year tenure of the program.
DESCRIPTION (provided by applicant):
Carbon nanoparticles (CNPs) are finding increased use in commercial, diagnostic, clinical and other applications. CNP production is anticipated to greatly increase and there is evidence of CNP formation by anthropogenic activity. However, evidence of their potential toxicity is also increasing and respiratory exposure is considered one route of exposure. A number of studies have now demonstrated that manufactured CNP (single walled carbon nanotubes (SWNT), multi-walled carbon nanotubes (MWNT) and to a lesser extent C60 carbon spheres (C60CS)) all cause pulmonary toxicity ranging from inflammation, granuloma formation, fibrosis and airway changes. Macrophages are considered potential targets of CNP in the Jung that may contribute to pathologic outcomes. In vitro toxicity of these particles has been demonstrated with a suggested rank order of potency most often SWNT> MWNT> C60CS. Although reports of nanoparticle toxicity are increasing, the results are often difficult to correlate since the sources (and compositions) and methods of suspension are different for CNP, and often only one particle type is examined. Furthermore, the mechanism(s) by which these uniquely hydrophobic particles are acting is unknown. Based on the unusual physical properties and size of the carbon nanoparticles, as well as our preliminary results with SWNT, MWNT and C60CS, we postulate that CNP are causing membrane disruption leading to changes in macrophage function contributing to lung inflammation. Furthermore, the different sizes of the CNPs may contribute to the rank order of potency and effects. In order to test these hypotheses and gain new information on mechanisms of action we propose the following goals.
1) Compare and evaluate how much variability in biological activity of CNP stems from differences in sources and methods of suspension.
2) Demonstrate that CNP cause alteration of membrane properties and function.
3) Evaluate the effects of CNP on macrophage function related to membrane activity.
The results of these studies will provide important new information regarding the roles that different CNP sources, suspension (disaggregation) protocols and CNP types have on membrane disruption. In addition, the studies will provide information on the mechanism of action in membranes how that translates to alterations of macrophage function.
The short-term goals of this application are to identify adducted and altered protein biomarkers that correlate
with organophosphate (OP) insecticide exposure and to use these biomarkers to generate antibodies to
validate the detection of these biomarkers in biological fluids. Over 100 million pounds of OP insecticides
are used each year but lead to over 25,000 reports to poison control centers each year including 10,000
involving children under age six. These reports only account for acute poisoning events and do not include
low dose or chronic exposures. In addition to general exposure and food contamination, the safety of OPs is
a large public health concern because OPs share chemical traits, structure and biological mechanism with
nerve gas agents. These concerns are elevated by an array of neurologic and non-neurologic sequelae that
have been reported in connection with exposure to OPs. To combat, monitor and provide therapeutic
intervention, a blood cholinesterase test (BCT) has been conducted for decades. However, the test is limited
and inadequate to assess OP exposure and its shortcomings identified by an EPA report questioned the
merit of the BCT and suggested the need to examine true biomarkers of exposure. At this time, there is a
serious void in effective tests of OP exposure. New tests are needed that are sensitive, selective, operate in
real time and are based on reliable, well-characterized OP-biomarkers derived from exacting molecular
events that correlate with cellular, tissue, organ or systemic toxicity.
The long range goal of our research is to identify OP-adducted and/or OP-altered protein biomarkers that are
associated with OP-induced sequelae and to develop diagnostic methods and tests that assess the human
health risk and aid therapeutic action. For the proposed grant period, we will address the following specific
aims: SA 1. Show that OP's result in highly specific OP-AChE adducts that can be identified and
differentiated by antibodies. SA2. Identify and characterize OP-adducted protein biomarkers in SH-SY5Y
neuroblastoma cells using OP-reporter molecules. SA3. Identify and characterize OP-protein biomarkers
from human saliva, human serum and human erythrocytes and SA4. Prepare customized antibodies that
recognize OP-adducted proteins identified in SA-II and SA-III and develop efficient diagnostic tests to identify
and quantify OP-protein adducts.
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