Word (http://tools.niehs.nih.gov/portfolio/sc/list_doc.cfm?ext=.doc)
|
Excel (http://tools.niehs.nih.gov/portfolio/sc/list_xls.cfm?ext=.xls)
|
PDF (http://tools.niehs.nih.gov/portfolio/sc/list_doc.cfm?pdf=1&ext=.pdf)
Record Count: 25
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): Elucidation of the specific steps involved in signal transduction pathways activated in cellular responses to DNA damage and other cellular stresses can provide critical insights into the genesis of malignancies and suggest new therapeutic approaches. Inhibitors of topoisomerase I have become an important component of our armamentarium in treating human cancers, however, little is known about the signal transduction pathways that participate in cellular responses to these agents. Experiments are proposed here that will elucidate the signaling pathways that are activated in cells following exposure to topoisomerase I inhibitors, including the roles of ATM and/or ATR and the numerous proteins that have been found to be downstream of these protein kinases in other cellular responses. Hypoxia is a cellular stress that plays a critical role in tumor development and appears to influence tumor prognosis. Studies are proposed that will also elucidate the cellular signaling pathways that determine cellular outcome in the presence of hypoxic stress. Since many of the steps in these pathways participate in controlling specific stages of the cell cycle, these characterizations should provide new insights into the nature of the cellular lesions that are present following exposure to these cellular stresses. P53 protein is one of the critical modulators of cellular responses to stress and a series of proposed experiments specifically address the regulation of p53 protein levels and function following DNA damage and hypoxia. In particular, continued or enhanced translation of p53 protein in the face of these stresses suggests a unique mechanism of translational regulation and the role of the 5'-UTR of p53 in this process will be investigated. In addition, experiments are proposed that will elucidate the importance of post-translational modifications of p53 protein and cellular redox status in controlling the ability of p53 protein to bind to specific DNA promoter sequences following stress. Finally, one of the major goals of understanding the molecular basis of these responses is to improve interventions in the treatment of cancer. Towards this end, responses of tumor xenografts with specific lesions in one or more of the signaling steps in these pathways will be examined. In tow, these studies should provide significant new information that has implications for both tumor development and therapy.
DESCRIPTION (provided by applicant): This Program Project seeks to understand mechanisms by which exposures to environmentally- and endogenously-produced bis-electrophiles, such as vinyl chloride, acrolein, crotonaldehyde, and 4- hydroxynonenal (4-HNE), induce genotoxic response, ultimately impacting human health. All organisms must successfully maintain a stable genome in the face of continuous insults arising from genotoxic chemicals. Adduction of DNA by these aldehydic bis-electrophiles yields interstrand crosslinks, interstrand crosslinks, DNA-protein conjugates, and various regioisomeric mono-adducts. These compounds likely contribute to background levels of inter- and /intrastrand crosslinks and DNA-protein crosslinks formed in human cells. The inability to repair genomic damage correlates with human disease-e.g., cancer, premature aging, fatty liver disease, and atherosclerosis. The three projects utilize complementary technologies to address common goals-understanding the mutagenic and cytotoxic consequences of DNA adduction by bis-electrophiles. Emphasis will be placed upon elucidation of the chemistry and biology of (1) interstrand and (2) intrastrand crosslinks formed by bis-electrophiles, and (3), examining the chemistry and biology of potentially highly mutagenic regioisomeric adducts formed by bis-electrophiles-particularly at N1-dA and N3-dC, and N7-dG, as compared to adducts formed at N2-dG. Project 1, led by Dr. Carmelo Rizzo, will develop novel synthetic routes to construct oligodeoxynucleotides containing site- and stereospecific inter- and intrastrand DNA crosslinks, and N1-dA and N3-dC, and N7-dG adducts of bis-electrophiles, will investigate the in vitro replication bypass and secondary chemical reactivity of these adducts, and will work to identify these adducts in cellular DNA. Project 2, led by Dr. Stephen Lloyd, will generate biological endpoints with respect to replication, repair, and mutagenesis in response to the introduction of these lesions into cells. The essential steps required for repair of interstrand crosslinks in the absence of homologous recombination will be determined. The mutagenic spectra of intrastrand crosslinks, and of N1-dA and N3-dC adducts will be determined in mammalian cells. The role of DNA sequence in modulating the mutagenic spectra will be examined in mammalian cells, with emphasis on frameshift-prone sequences. The biological processing of interstrand crosslinks will be examined. Project 3, led by Dr. Michael Stone, will provide structural data for oligodeoxynucleotides containing inter- and intrastrand crosslinks using a combination of NMR and X-ray crystallographic approaches. The interactions of modified DNA templates with bypass polymerases will be determined. Interactions between the three projects will be iterative, with biological data from Project 2 focusing synthetic priorities in Project 1 and structural priorities in Project 3. Project 1 will provide novel adducts for the biological and structural studies, and access to DNA modified with these adducts, via the DNA Synthesis Core Facility.
DESCRIPTION (provided by applicant): Styrene and butadiene, used in the production of rubber and plastics, are implicated in the etiology of human cancer. Butadiene is classified by the USEPA as "carcinogenic to humans by inhalation", by the NTP as a "known human carcinogen". Chronic occupational exposures to mixtures of styrene and butadiene correlate with risk for leukemias. This project will examine the etiology of butadiene-induced mutagenesis, developing structure-activity relationships for DNA adducts arising from butadiene epoxides and associated with human genotoxicity. The first aim will combine NMR, crystallography, and biochemical approaches to examine N1- deoxyinosine adducts arising from deamination of N1-deoxyadenosine alkylation products. We propose a role for Y-family Pol i utilizing the Hoogsteen face of dl for templating, allowing incorporation of protonated dCTP or dATP. The second aim will employ NMR and crystallographic approaches to examine stereoisomeric N3-dU adducts of butadiene monoepoxide, which arise from deamination of N3-dC adducts. We propose that they do not undergo rotation about the glycosyl bond, into the syn conformation, thus leading to fundamentally different biological and mutagenic outcomes. The third aim will use NMR, biochemical, and site-specific mutagenesis to examine N7-dG adducts arising from exposures to butadiene epoxides. Emphasis will be placed on relationships of N7-dG adduction to the formation of interstrand and intrastrand crosslinks by butadiene diepoxide; this depends upon DNA sequence and diepoxide stereochemistry. Interstrand crosslinks form in 5'-GNC-3' sequences. We propose that the orientations of N7-dG butadiene diol epoxide mono-adducts depend upon stereochemistry, differentially orienting the diol epoxides for interstrand vs. intrastrand crosslinking. The chemistry, mutational spectra, and replication bypass of N7-dG FAPy re-arrangement products will be examined. Overall, we will delineate mechanism(s) by which N1-dl and N3-dU butadiene adducts induce mutations, and why specific polymerase(s) mediate lesion bypass. Insight will be gained into DNA crosslinking chemistry of butadiene diepoxides. Insight will be gained into the chemistry of butadiene N7-dG FAPy lesions, their biological processing, and their structures. This is essential to understanding how occupational exposures to mixtures of styrene and butadiene contribute to human genotoxicity and cancer etiology.
DESCRIPTION (provided by applicant): Many carcinogens become covalently attached to DNA and cause genotoxic damage due to polymerase blockage or nucleotide misincorporation. These events are controlled kinetically by the individual DNA polymerases. Continued studies are proposed on the interaction of a series of carcinogens, bound to oligonucleotides, with a set of both replicative and so-called translesion bypass polymerases, including viral (DNA polymerase T7-, HIV-1 reverse transcriptase) and bacterial (Dpo4) model polymerases as well as recombinant human polymerases (delta, eta, iota, kappa, REV1). Kinetic analyses will be done with these polymerases and the 22 DNA-carcinogen adducts available, varying in size from oxygen and methyl groups to large polycyclic hydrocarbons, identifying changes in rate-limiting events related to normal incorporation vs. misincorporation and blocking. The working hypothesis is that alternate conformations and inactive complexes are important, and some of these may also have rapid nucleotide dissociation kinetics. Another use of kinetic analysis will be to understand the chronology and coupling of the events involved in changing polymerases at DNA damage sites, i.e. between replicative and translesion polymerases. Roles of accessory proteins will be considered. Pre-steady-state kinetic spectroscopic approaches will also be used to better define events related to individual steps of polymerase catalysis, with fluorescence and circular dichroism changes being compared to measured rates of product formation. Work on the crystallography of carcinogen-adducted DNA with polymerases (HIV-1 reverse transcriptase, Dpo4) is in progress and will be expanded, with the goal of linking temporal events with specific structural changes. The general working hypothesis is that normal incorporation, misincorporation, pausing, and blockage represent a continuum of events related to fits and rates of reactions involving polymerase-DNA-dNTP ternary complexes, and that these can be understood in quantitative terms (rate constants and structures). The overall goal is understanding molecular mechanisms of mutagenesis and relevance to chemical carcinogenesis.
DESCRIPTION: Many halogenated hydrocarbons are of interest because of their
high production volume and demonstrated ability to cause cancers in
experimental animals. The vinyl halide trichloroethylene (TCE) can be activated
via oxidation or conjugation; the focus in this proposal will be on oxidation
and the key product TCE oxide. The mechanism of TCE oxide hydrolysis will be
established using kinetics and isotope labeling patterns. Reaction products
formed with proteins and DNA will be characterized with the working hypothesis
that acyl halides are the major electrophiles that react. Dihalomethanes
(CH2X2) are activated by enzymatic glutathione (GSH) conjugation. The
characterization of CH2X2-derived GSH-DNA adducts will be done using mass
spectrometry, with work extended to in vitro settings with CH2Cl2. Rat and
human GSH transferases will be compared (in terms of DNA adduction) with a
bacterial analog (DM11) that allows for growth of Methylophilus on CH2Cl2. This
work and structure-activity relationships among CH2X2 compounds will be done to
help establish the conjugation mechanism and to determine if GSCH2X or HCHO is
the genotoxic product (of CH2X2). Other work will involve a search for
GSH-containing DNA adducts derived from 4-carbon bifunctional electrophiles
(e.g. butadiene diepoxide) as an explanation for enhancement of bacterial
mutation by GSH transferase expression. Work with ethylene dibromide (EDB) will
involve (i) completion of bacterial site-directed mutagenesis work with guanyl
N2-, N7-, and O6-CH2CH2SG adducts to determine the relative contributions of
each and (ii) analysis of the basis of O6-alkylguanine tranferase-increased
mutagenicity of EDB (and CH2Br2). These experiments involving enzymatic
oxidation and conjugation reactions are intended to help define important
concepts that can be applied to other halogenated hydrocarbons and to other
cancer suspect chemicals as well.
Crisp Terms/Key Words: laboratory rat, chemical conjugate, adduct, crosslink, chemical kinetics, hydrolysis, mass spectrometry, enzyme structure, site directed mutagenesis, gene expression, gene mutation, halohydrocarbon, trichloroethylene, stable isotope, chemical model, oxidation, epoxide, high performance liquid chromatography, radiotracer, environmental toxicology, glutathione transferase, technology /technique development, DNA damage, enzyme activity, methylguanine DNA methyltransferase
Funding is requested for the continued support of the NIEHS Center at Vanderbilt University, which has been in existence and continuously supported by the NIEHS since 1967. The scientific base is the Center in Molecular Toxicology, an interdepartmental unit of investigators drawn from several departments in the School of Medicine and the Department of Chemistry. Currently, there are 16 named Center Investigators in the program from the Departments of Biochemistry, Chemistry, Medicine, and Pathology. These Center Investigators lead the programs, and the influence of the Center is extended to a larger base at the institution and in the community
through collaborations and sharing of expertise. Current Research Cores include (i) Enzymatic Oxidation and Conjugation, (ii) Oxidative Damage, (iii) DNA Damage and Mutagenesis, (iv) Mechanisms of Cell Signaling, and (v) Structural Biology. Each Research Core is led by a Center Investigator and involves projects of Center Investigators and others. Service Core Facilities include (i) NMR and Crystallography, (ii) Mass Spectrometry, (iii) Proteomics, (iv) Molecular Recognition, and (v) Cell Biology. Other units include Administrative, Director's Office, and New Investigators. The Community Outreach and Education Program developed considerably during the course of the previous grant period and will be expanded further. The Center grant also supports a Pilot Project program, seminars and symposia, and other items aimed at strengthening programs at Vanderbilt relevant to environmental health science research. During the current grant period, four Center Investigators were recruited to Vanderbilt. A strong toxicology training program is in place. Major interactions at Vanderbilt involve the Division of Clinical Pharmacology, the Vanderbilt-Ingram Cancer Center, the Clinical Nutrition Research Unit, the Middle Tennessee Poison Control Center, and other programs. The overall focus of the NIEHS Center at Vanderbilt is basic chemical and biological aspects of molecular toxicology, with an emphasis on relevance to human health.
Crisp Terms/Key Words: environmental toxicology, biomedical facility, clinical research
DESCRIPTION (provided by applicant):
Lipid Peroxidation and Antioxidant Mechanisms is a competitive renewal proposal for an NIEHS Program- Project that was funded in September of 2005. Environmental stress and lifestyle play an important role in diseases that contribute significantly to mortality in the U.S. Cigarette smoking, alcohol consumption and poor diet combine with other environmental factors to affect the incidence of several diseases. The formation of oxidants is a hallmark of many of these diseases and lipid peroxidation is a common result of diverse environmental insults. Indeed, oxidative stress has been closely associated with the onset of pathologies as diverse as cancer and cardiovascular disease. The underlying mechanisms linking environmental stresses with disease pathogenesis remain obscure. The studies proposed here will test the hypothesis that the balance of competing oxidation pathways for different lipid substrates governs adaptation to oxidative stress and oxidative injury. The Program Project also directly addresses the hypothesis that protein adduction by lipid peroxidation products alters cellular signaling and modulates diseases linked to oxidative stress. This Program Project includes four research projects and one scientific core facility in a tightly-knit group that will provide important insights into the role that oxidation and antioxidants play in human pathophysiology. Project 1 provides a mechanistic framework for understanding peroxidation profiles and leads the chemistry that provides novel lipid affinity-tags for studying protein-electrophile adducts. Project 2 explores the chemistry and biology of eicosapentaenoic acid (EPA), a fatty acid prominent in fish oil, and explores the hypothesis that EPA oxidation products may contribute significantly to the biological properties of this fatty acid. Project 3 evaluates electrophiles that play critical roles in cell signaling and provides the biological platform for studying lipid affinity tags in whole cells. Project 4 suggests that secondary electrophilic products of lipid peroxidation play critical roles in oxidant-associated molecular pathologies and explores methodologies for identification and analysis of protein adducts of these electrophiles. All of the projects are highly collaborative and are highly dependent on the Lipidomics Analysis scientific core.
BACKGROUND
This is a renewal application of a Program Project Grant by a highly integrated team of investigators, led by Dr. Porter, which was initially funded in 2005. The PPG seeks to continue studies towards the mechanisms of lipid oxidation and the role of lipid-derived electrophiles in biological responses to oxidative stress, using innovative strategies and advanced analytical tools to identify biological targets for lipid-derived electrophiles. Although the original proposal was requested for a 5-year period, and the previous review team unanimously recommended reduction to 3 years, in order to focus on development of tools and analytical strategies and for subsequent use in biological studies. The current application consists of 4 Projects, led by the same investigators as in the original application, and includes 2 Cores, an Administrative Core and a newly added Lipidomics Analytical Core, which replaces the original Mass Spectrometry and Proteomics Core.
PROGRAM AS AN INTEGRATED EFFORT
DESCRIPTION (provided by applicant): Benzo[a]pyrene (BaP) is an environmental pollutant. Besides inducing cancers in humans, BaP has been shown to promote the development of atherosclerosis, which is the primary cause of coronary heart disease and stroke. The mechanism underlying the atherogenic action of BaP remains unknown. A currently popular theory postulates atherosclerosis as an inflammatory process driven by reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. BaP has been shown to increase intracellular ROS. Thus, the project described herein hypothesizes that generation of ROS in vascular cells is a key mechanism by which BaP promotes atherogenesis. Our laboratory has generated mouse models that overexpress Cu/Zn-superoxide dismutase (Cu/Zn-SOD) or catalase alone, or both Cu/Zn-SOD and catalase. Cu/Zn-SOD is a protein that converts superoxide to hydrogen peroxide, while catalase destroys hydrogen peroxide by converting it to water. As the relative contribution of different ROS to atherosclerosis might vary, our animal models provided a valuable tool for testing the role of superoxide and hydrogen peroxide in BaP-induced atherosclerosis. The transgenic mice overexpressing Cu/Zn-SOD and/or catalase have been crossbred into the apolipoprotein E (ApoE)-deficient mice, which spontaneously develop atherosclerotic lesions with morphological features closely resembling the atherosclerotic lesions that occur in humans. In this project, the ApoE-deficient mice, with or without overexpression of Cu/Zn-SOD and/or catalase, will be treated with BaP. We will determine: (1) whether overexpression of antioxidant enzymes inhibits BaP-induced atherogenesis and reduces the accumulation of inflammatory cells within the atherosclerotic lesions, (2) whether overexpression of antioxidant enzymes reduces BaP-induced accumulation of oxidized lipids and nitrotyrosine in the arterial wall, and (3) whether overexpression of antioxidant enzymes reduces BaP-induced atherogenic events in vascular cells, and inhibits BaP-induced gene expression and transcriptional factor activation. If our hypothesis described above is correct, BaP-induced atherosclerotic lesions will be smaller in mice overexpressing Cu/Zn-SOD and/or catalase, which will correlate to a decreased oxidative injury in the arterial wall and/or a reduced response of vascular cells to BaP.
DESCRIPTION (provided by applicant): Abstract: Exposure to volatile organic compounds (VOCs) occurs commonly in everyday life. Accurate assessment of the risk to public health posed by VOCs requires both the quantification of these exposures on a population-wide basis and the evaluation of potential health effects associated with varying exposure levels. Preliminary analyses that we have done show that in the NHANES III data an association exists between blood levels of selected VOCs and abnormal liver function tests. We propose to conduct a thorough examination of the potential effects of personal exposure to VOCs on liver function, using the data from NHANES 1999-2000. We will investigate whether there are independent effects or if the effects are modified by alcohol consumption and use of pain medications. In addition, we will examine the associations between exposure to a cluster of VOCs and biochemical markers of liver function after grouping toxicologically similar VOCs. VOC exposure status will be described according to the personal monitoring data for ten VOCs. Biochemical markers of liver function included serum concentrations of albumin, bilirubin, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, and 3-glutamyl transferase. Levels of these biomarkers will be compared by different exposure levels. Multiple linear regression and logistic models will be used to examine whether there is a linear association or a threshold effect which occurs only at relatively high levels of exposure. The analyses will also be performed for subgroups. By examining the relationship of sensitive markers of liver function and individual exposure monitoring data in a large national sample, this proposed study is able to detect a subtle/subclinical effect of VOCs at relatively low exposure levels. The assessment of possible interactions of VOC exposure with alcohol consumption and medication use may help to identify susceptible subgroups. If the effect of background VOC exposure on liver function is identified, then regulation can be used to reduce the exposures implicated. If it is confirmed that liver-enzyme elevations in asymptomatic people are linked with environmental exposure to volatile organic compounds, the finding will be very useful to both individual and public health. Narrative We propose to conduct a thorough examination of the potential effects of personal exposure to VOCs on liver function, using the data from NHANES 1999-2000. By examining the relationship of sensitive markers of liver function and individual exposure monitoring data, this proposed study may be able to detect a subtle effect of VOCs at relatively low exposure levels. If the effect of background exposure on liver function is identified, then regulation can be used to reduce the exposures implicated.
DESCRIPTION (provided by applicant): Human exposure to dithiocarbamates occurs in agriculture, industry and medicine. Although an understanding of degradative and metabolic pathways is evolving, there is currently little knowledge on the molecular targets and mechanisms underlying the biological affects of dithiocarbamates. The long-range objectives of this project are to delineate the interactions of dithiocarbamates and their metabolites within biological systems and to determine the relevance of these interactions as mechanisms of toxicity and biomarkers. Previous studies revealed the ability of certain dithiocarbamates to produce selective Schwann cell toxicity accompanied by increased levels of copper and lipid peroxidation products in nerve. Investigations in this application are guided by the working hypothesis that these dithiocarbamates bind endogenous copper, form lipophilic complexes and accumulate within myelin resulting in increased lipid peroxidation, oxidative injury and demyelination. This hypothesis will be tested through two specific aims: 1) To determine if copper accumulation and oxidative stress are required for dithiocarbamate-mediated segmental demyelination and 2) To determine the molecular targets and cellular responses in dithiocarbamate-mediated peripheral nerve demyelination. Aim 1 will be achieved through: a) synthesis of dithiocarbamates differing in their affinity for copper and their copper complex solubility and evaluating their relative potency for lipid peroxidation and demyelination in vivo, b) determining the ability of the non-dithiocarbamate copper chelating agent, cuprizone, to elevate copper and lipid peroxidation in nerve, c) determining if lipid peroxidation and copper accumulation are direct affects of dithiocarbamates through defining the dose response and temporal relationship of these affects to the onset of myelin injury and d) determining if transgenic models with compromised defense to oxidative injury and copper toxicity are more sensitive to dithiocarbamate-mediated demyelination. Aim 2 will be achieved through a) determining changes in protein expression, b) identifying damaged proteins, c) measuring cuproenzyme activities and d) characterizing the location and chemical species of excess copper produced in nerve by dithiocarbamates. The significance of these studies lies in establishing structure-activity relationships useful for predicting agents that may act through similar mechanisms, identifying susceptible populations, developing mechanistically based exposure recommendations and predicting the affects of long term low level exposures.
Crisp Terms/Key Words: proteomics, bioaccumulation, morphometry, neurotoxicology, oxidative stress, enzyme activity, toxin metabolism, environmental toxicology, thiocarbamate, posttranslational modification, pesticide biological effect, myelinopathy, intermolecular interaction, copper, chelating agent, metal complex, lipid peroxide, metalloenzyme, chemical structure function, chemical stability, disulfide bond, chemical binding, adduct, biomarker, genetically modified animal, laboratory rat, laboratory mouse
DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a global pollutant and potent neurotoxin whose abundance in the food chain mandates additional studies on the consequences and mechanisms of its CNS toxicity. Formulation of our new hypotheses was predicated on our appreciation for (a) the remarkable affinity of mercurials for the anionic form of sulfhydryl (-SH) groups, (b) the essential role of thiols in protein biochemistry, and (c) the role of molecular chaperone proteins, such as heat shock protein 90 (Hsp90), in the regulation of protein redox status by facilitating the formation and breakage of disulfide bridges. Given the high affinity of MeHg for thiols, we hypothesized that MeHg interferes with Hsp90 chaperone function resulting in altered cellular homeostasis and neurotoxicity. Among the client proteins known to bind to Hsp90 are type I (neuronal) nitric oxide synthase (NOS), and cytosolic prostaglandin E synthase (cPGESIp23). Additionally, Hsp90 reduces the mitochondrial electron transport protein, cytochrome c (cyt c). The specific aims are to [1] demonstrate that MeHg physically binds to Hsp90, altering Hsp90 chaperone function. [2] Determine whether MeHg increases the activity of the cPLA2-cyclooxygenase-1 (COX-1)-PGES enzymatic pathway resulting in enhanced prostaglandin E2 (PGE2) production by altering the binding of Hsp90 to PGES/p23. [3] Demonstrate that by altering the association between Hsp90 and neuronal NOS (nNOS) MeHg uncouples nNOS activity, resulting in NOS-derived superoxide (-O2) production and reduced NO bioavailability. [4] Determine whether MeHg-induced oxidant stress occurs via inhibition of the mitochondrial electron transport chain, causing increased -O2 production and reduced levels of the intracellular antioxidant, glutathione. The experimental approach includes cell-free lysates, rat-derived in vitro astrocyte, neuron, and astrocyte/neuron co-cultures, as well as in vivo corroborative studies in the rat. MeHg-mediated alterations in Hsp90/client protein interactions offers an innovative and unifying mechanism integrating the known propensity of MeHg to form complexes with -SH-containing ligands and MeHg-induced oxidant stress, mitochondrial dysfunction and CNS toxicity. The results of these studies will shed new light on meaningful mechanisms of MeHg-induced neurotoxicity, and pave the way for new pharmacological modalities for treatment. Additionally, studies on altered post-translational modification of Hsp90 client proteins might offer new mechanistic insight into other neurodegenerative disorders, and therefore they have broad biological implications
DESCRIPTION (provided by applicant)
The long-term objective of the proposed work is to understand how environmental and genetic factors interact to influence selective neuropathology. The work contained within this proposal focuses on the influence of manganese (Mn) exposure on the pathophysiology of Huntington's disease (HD). Mn over-exposure has been associated with changes in iron homeostasis and energy metabolism, and has been shown to promote the aggregation of intrinsically amyloidogenic proteins. Furthermore, a major site of Mn accumulation in the brain is the corpus striatum, which contains the neurons most vulnerable in HD. The chronic neurotoxic stress rendered by the mutant HD gene has been associated with alterations in iron homeostasis, deficits in cellular energy metabolism, and accumulation of the disease protein into amyloid-like inclusions. These similarities in the pathophysiology of HD and Mn neurotoxicity suggest a potential for Mn exposure to modulate HD neuropathology. Using pilot project resources provided by the National Institute of Environmental Health Sciences (NIEHS) Core Center in Molecular Toxicology at Vanderbilt University, the investigators tested the influence of increased Mn exposure on a striatal cell model of HD. These pilot experiments revealed a surprising and exciting result, that mutant HD striatal cells are resistant to Mn toxicity and pathophysiologically relevant exposures to Mn suppress mutant HD phenotypes. This proposal will utilize cellular and mouse models of disease to examine the molecular basis of this gene-environment neuroprotective interaction and evaluate the potential of Mn exposure to modulate HD pathogenesis. These studies are organized around three specific aims. In the first of these the investigators will define the contribution of specific HD protein domains and specific cellular mediators of Mn action to the Mn-HD gene-environment interaction by functional domain mapping and evaluating other metals with similar neurotoxic properties. In the second aim the investigators will determine if Mn ions alter the conformational or functional properties of the HD protein by biochemical and biophysical protein assays utilizing cellular and animal models of HD. Then, in the third aim the investigators will evaluate known pathological endpoints of Mn toxicity and HD neuropathology to elucidate the physiological processes that underlie the Mn-HD interaction in vivo. These specific aims are aligned with the mission of the NIEHS in that they examine the impact of a specific environmental toxicant on the pathophysiological processes of human disease. Finally, by exploring a gene-environment interface that moderates the onset and progression of HD, this study seeks to reveal mechanistic detail for how convergent genetic and environmental factors can enhance or suppress disease.
DESCRIPTION (provided by applicant): Manganese (Mn) is an essential metal needed for normal growth and development. Excessive environmental or dietary exposure results in Mn deposition in Mn-sensitive brain regions causing adverse psychological and neurological effects. Sick infants requiring parenteral nutrition (PN) may be at increased risk of Mn neurotoxicity because neonatal PN solutions contain high concentrations of Mn, PN bypasses the normal intestinal absorptive control and biliary excretory mechanisms for Mn, and infants are at a critical stage of brain development. Furthermore, iron (Fe) deficiency, a common problem among sick neonates, increases Mn brain uptake because Mn and Fe compete for the same carrier transport systems in the central nervous system. The long term goals of this project are to identify neonatal populations that are at increased risk of excessive brain Mn deposition based on their gestational age, iron status, hepatic function and dietary Mn intake, and to make evidence-based recommendations for appropriate Mn supplementation and monitoring of infants receiving PN. This proposal will investigate brain deposition of Mn, a paramagnetic element, by magnetic resonance (MR) imaging in 40 neonates receiving Mn-supplemented PN and 10 control infants. Two specific aims will test the following hypotheses: (1) shortening of MR T1 and T2 relaxation times (a marker for Mn) in selective Mn-sensitive brain regions in neonates receiving PN will correlate directly with (a) dietary Mn intake, (b) days on PN, (c) blood Mn levels (measured by Inductively Coupled Plasma-Mass Spectrometry) and (d) hepatic dysfunction/cholestasis (assessed by conjugated bilirubin levels). (2) shortening of T1 and T2 relaxation times will correlate inversely with (a) gestational age and (b) Fe status (assessed by serum Fe, ferritin, transferrin, soluble transferrin receptor and hemoglobin). The potential for increased brain Mn accumulation in infants and the potential health risks associated with elevated brain Mn burden represent crucial, unexplored issues of exposure and susceptibility. The impact of dietary Mn, and especially parenterally delivered dietary Mn, gestational age, Fe status, and hepatic dysfunction on the ability of the neonatal brain to regulate Mn deposition has not been scientifically addressed. The proposed clinical investigation has enormous health significance and may shed light on the development and progression of neurological dysfunction in infants and children on prolonged parenteral nutrition.
Crisp Terms/Key Words: white matter, brain morphology, environmental exposure, bioimaging /biomedical imaging, clinical research, cholestasis, environmental toxicology, gestational age, longitudinal human study, magnetic resonance imaging, dietary supplement, infant nutrition disorder, nutrition related tag, parenteral feeding, developmental neurobiology, metal poisoning, manganese, metal metabolism, liver disorder, iron metabolism, human subject, newborn human (0-6 weeks), infant human (0-1 year), mass spectrometry, brain imaging /visualization /scanning, brain metabolism, lenticular nucleus, bilirubin
DESCRIPTION (provided by applicant): In accordance with the goals set forth by NIEHS, this project seeks to examine the role of pesticides in the etiology of Parksinon's disease (PD). Numerous reports have suggested a link between the on-set of PD and an agricultural environment, which includes pesticide usage. Patients with PD are also known to have mitochondrial dysfunction. Interestingly, many argochemicals are also known mitochondrial inhibitors. The long-term goal of this project is to understand the relationship of two toxicants, the fungicide maneb and the glyphosate-containing herbicide Roundup, to neuronal toxicity. Using the nematode Caenorhabditis elegans (C. elegans) as a model organism, we will test the hypothesis that exposure to multiple agrochemicals, specifically maneb and Roundup, leads to neuronal degeneration. Additionally, we hypothesize that sequential exposure to these pesticides leads to increased oxidative stress. The hypothesis will be tested through two specific aims: (1) to determine whether exposure to maneb or Roundup affects neuronal populations known to be vulnerable in either PD or manganese neurotoxicity; and (2) to determine whether exposure to maneb or Roundup induces the up-regulation of proteins associated with the production of oxidative stress. In order to complete this study, we will use genetically modified C. elegans with various neuronal populations or antioxidant proteins tagged with green fluorescent protein (GFP). Worms will be exposed to varying concentrations of maneb or Roundup, separately, to determine whether they induce neuronal degeneration or oxidative stress as assessed by fluorescent microscopy. Subsequent studies will examine whether sequential treatment of these two pesticides results in increased toxicity. Results from these novel studies will further our understanding of the neurotoxic effects of multiple pesticide exposures. Additioanlly, they will provide evidence about this ability of these chemicals to induce mitochondrial inhibition in vivo. It is anticipated that data gleaned from these studies will further our understanding not only of pesticide neurotoxicity, but also of the mechanism through which environmental toxicants may facilitate the etiology of idiopathic Parkinson's disease. These studies are particularly important to public health because of the increased use of Roundup, and similar herbicides, by the general public and the agricultural community. Although the main ingredient in Roungup is relatively non-toxic, recent data shows that when the chemical is mixed for commercial usage, the final product may be more toxic. Additionally, this work will examine the effects of exposure to multiple pesticides, which is more likely to occur in human exposures.
DESCRIPTION (provided by applicant): The nutritional effects of selenium depend on selenoproteins. Selenoprotein P (Se-P) is an extracellular selenoprotein that has been postulated to transport the element from the liver to other tissues. In past grant periods we have shown that Se-P accounts for most of the selenium flux through rat plasma and that the brain up regulates its acquisition of selenium from Se-P in selenium deficiency. In the present grant period, we have identified a heparin binding site and 4 glycosylation sites on rat Se-P. We have characterized 4 isoforms of Se-P. Three of them terminate at UGAs in the mRNA and the 4 tb is full length. This indicates that some UGA codons have alternative functions of termination and designation of selenocysteine insertion. We have also produced mice with deletion of the Se-P gene (Sepp). Sepp -/ mice have male infertility. When fed a low selenium diet, they develop axonal degeneration in the brain stem with severe neurological dysfunction. Testis and brain have low selenium concentrations in Sepp -/- mice, indicating that both organs depend on Se-P for some of their selenium. We propose to characterize selenium homeostasis, using Sepp -/- mice and mice with deletion of the other plasma selenoprotein, GPX-3, with special emphasis on the brain. This will pinpoint regions of the brain dependent on Se-P (and possibly GPX-3) for selenium. Using immunoaffinity methods, we will seek to identify a receptor for Se-P in the brain and to characterize it. Then the receptor will be mapped using immunocytochemistry. We will use morphological methods to determine brain regions in which cells degenerate in Sepp -/- mice fed a low selenium diet. Results of these studies will be interpreted to characterize the brain injury with the objective of selecting human neurological disorders to study for genetic abnormalities of Se-P and its receptor.
DESCRIPTION (provided by applicant): The etiology of Parkinson's disease (PD) involves gene/environment interaction. While most of the identified genetic mutations affect the ubiquitin-proteasome system (UPS), epidemiological studies and clinical case reports have strongly suggested the association between pesticide exposure and increased incidence of PD. In animal models, selective toxicities to the nigrostriatal dopaminergic neurons occur after systemic exposure to rotenone and paraquat. Oxidative stress is a common mediator of pesticide-induced neurotoxicity. It contributes to PD-related pathological changes such as formation of a-synuclein aggregates and inhibition of proteasomal function. However, the molecular targets of oxidative damage have not been clearly defined and the mechanistic link between mitochondria! and proteasomal dysfunction remains to be determined. In our preliminary studies, we have shown that mitochondrial thioredoxin (mtTrx; Trx2) is particularly susceptible to oxidation induced by a variety of environmental toxicants, including peroxides, rotenone, MPP+ and paraquat. Submicromolar concentrations of rotenone induced persistent oxidation of mtTrx and redistribution of mtTrx to the cytoplasm. Chronic exposure to nanomolar concentrations of rotenone resulted in decreased mtTrx protein. Overexpression of mtTrx protected cells from oxidant-induced apoptosis and inhibited a-synuclein aggregation caused by chronic rotenone toxicity. Downregulation of the mitochondrial thioredoxin reductase (TrxR 2) led to decreased mature mtTrx while increased its precursor form. Furthermore, we identified that mtTrx interacted with mitochondrial heat shock protein 60 which is a key component of the mitochondrial protein processing machinery. Based on these findings, we hypothesize that selective targeting of mtTrx by pesticides and the ensuring oxidation of mtTrx lead to impaired mitochondrial protein import. The hypothesis will be tested with two specific aims. Specific aim 1 is to determine whether the redox status and expression level of mtTrx control the sensitivity to pesticide-induced toxicity in cultured neuronal cells. Specific aim 2 is to determine whether the pesticide-induced oxidation inhibits the import of mtTrx and other nuclear DMA-encoded mitochondrial proteins. Results from these studies will define novel protein targets of oxidative injury and will facilitate our understanding towards the molecular mechanisms of environmental toxicities associated with PD.
DESCRIPTION (provided by applicant): Upwards of 1 billion dollars are spent each year in the U.S. diagnosing and treating women with endometriosis who often suffer from both severe pain and infertility. Only menstruating species, including humans and primates, exhibit naturally occurring endometriosis and the disease rarely persists in the absence of ovarian steroid production. Although the exact incidence of endometriosis is unknown, the disease occurs more frequently in industrialized countries, likely reflecting environmental contamination with endocrine disrupting chemicals such as dioxin (TCDD; 2,3,7,8 tetrachlorodibenzo-p-dioxin). Numerous studies have suggested a possible link between exposure to TCDD and the development of endometriosis, although epidemiologic data has been conflicting. Our studies indicate that endometrial progesterone resistance plays a significant role in the establishment and progression of endometriosis. Intriguingly, normal endometrium that has been exposed to TCDD mimics several key features of endometrial tissue from women with endometriosis, including an increased expression of matrix metalloproteinases (MMPs). Specifically, we have found that TCDD activates an epithelial-dominant pathway of cell-cell communication which reduces endometrial sensitivity to progesterone and promotes MMP-mediated establishment of experimental endometriosis in nude mice. The extent to which exposure to TCDD in human populations affects endometrial function related to a woman's risk for developing endometriosis remains unknown. To address this issue, we propose to use our established cell culture models and nude mouse experimental disease model to explore the role of TCDD as a progesterone disrupter in the human endometrium. We will also utilize our nude mouse model to examine the affect of TCDD on the invasive behavior of human endometrial tissue, a requirement for the establishment of endometriosis. To accomplish these goals, we propose the following specific aims: 1) to determine whether reduced progesterone responsiveness in the endometrium of women with endometriosis increases the toxicity of TCDD on MMP regulation and 2) to determine whether reduced progesterone sensitivity in the endometrium of women with endometriosis increases the toxic impact of TCDD on the synthesis of retinoic acid during stromal decidualization in vitro and 3) to correlate TCDD-mediated activation of epithelial-dominant cell-cell communication with the invasive behavior of stromal and epithelial cells in an experimental model of endometriosis.
DESCRIPTION (provided by applicant): Reactive electrophiles generated by environmental agents and stresses can modify proteins and trigger adaptive cellular responses reflected by gene expression and protein functional changes. Cysteine thiol groups are thought to be key sites of important oxidative or covalent adduct modification, but the specific structural characteristics that cast proteins in sentinel roles are unknown. The overall objective of this project is to identify specific protein targets that serve as triggers for cellular stress responses. We hypothesize that specific structural features allow some alkylation sensitive proteins to act as "sensor-triggers" that readily react with electrophiles and that adduction alters critical protein-protein interactions, thus causing changes in kinase signaling and transcription factor regulation. We will use new proteomics liquid chromatography-tandem mass spectrometry (LC-MS-MS) tools and approaches to study the mechanisms by which protein modifications alter key protein-protein interactions that regulate stress responses. The specific aims of the proposed research are: 1) To identify protein classes, sequence motifs and domain structures that are targets for thiol-reactive electrophiles in human cells. Biotin-linked electrophiles will be used to combine affinity enrichment and new LC-MS-MS approaches to identify modified proteins and map the adducts to specific sequences. Different thiol-reactive electrophile chemistries will be used to establish the generality of the targets identified. Bioinformatics tools will be used to associate adducted sequences with specific domain structures and motifs. 2) To validate specific proteins as targets for thiol-reactive electrophiles in intact cells. Proteins identified as targets for biotin-linked electrophiles in Specific Aim 1 will be evaluated as targets for model electrophiles that correspond to their biotin-linked counterparts in cell models. 3) To characterize the effects of protein adduction on selected protein enzymatic activities and on selected protein-protein interactions in reconstituted systems in vitro. Quantitative proteomics methods will be applied to compare adduction with changes in target activities and protein-protein interactions in a parallel in vitro model. These studies will lay the groundwork for applying molecular target analysis to proteomes in toxicology.
Crisp Terms/Key Words: bioinformatics, liquid chromatography mass spectrometry, protein protein interaction, enzyme activity, environmental stressor, protein structure function, protein kinase, transcription factor, gene expression, adduct, alkylation, proteomics, thiol, protein sequence, biological signal transduction
DESCRIPTION (provided by applicant)
Environmental exposures play a critical role in the pathogenesis of many common complex diseases. The purpose of the proposed Vanderbilt Environmental Health Science Scholars (VEHSS) program is to develop patient-oriented researchers committed to a career in environmental health research and equipped to function within and lead multidisciplinary teams of researchers to enhance understanding of environmental disease and to improve health. The VEHSS will focus on two specific scientific themes: 1) the role of oxidative stress in environmental injury/exposure and 2) mechanisms of environmental neurotoxicity. Vanderbilt investigators have developed and validated unique biomarkers of oxidative stress, a process implicated in the pathogenesis of many common diseases. Likewise, Vanderbilt investigators have elucidated mechanisms of metal transport and oxidative stress to better understand adverse developmental and neurodegenerative effects of environmental exposures. In each focus area of patient-oriented environmental health sciences research, Scholars will be trained in 1) a multidisciplinary approach, drawing on expertise in human genetics to identify gene-environment interactions, 2) proteomics, lipidomics, and state-of-the-art mass spectrometry techniques to discover biomarkers of environmental exposure and disease states, 3) cutting-edge imaging techniques to analyze tissue uptake of metal ions and toxins and local metabolic consequences, and 4) informatics and biostatistics to analyze large and complex data. The current proposal provides a unique opportunity to merge Vanderbilt's strengths in basic environmental health sciences research and patient oriented research to create a training program that can have a major impact on environmental health in the United States. Thus the goals of the VEHSS program are to: 1) Integrate Vanderbilt's well-established, strong basic science programs in toxicology and environmental health sciences with its equally significant accomplishments in patient-oriented research to increase the impact of environmental health sciences research to improve human health. 2) Develop a unique didactic core in research methodology for conducting hypothesis-driven research in environmental health and capitalize on existing career development resources to develop a cadre of leaders in multidisciplinary patient-oriented research in environmental health sciences. 3) Leverage the shared resources of the Vanderbilt-Meharry Alliance to increase the number of underrepresented minorities serving as Scholars and Mentors and leaders in environmental health sciences research.
DESCRIPTION (provided by applicant)
This T35 grant application is designed to support medical students involved in a Summer Research and Training Program in Environmental Health Sciences. The proposed program will capitalize on the outstanding research facilities at the Vanderbilt University, School of Medicine, strengths in environmental health coupled with patient-oriented research, existing research and training infrastructure, and a demonstrated institutional commitment to the continued development of biomedical research and training. Funds are requested to support ten pre-doctoral short-term trainees per year (M.D. candidates).
The list of preceptors includes twenty-eight faculty members representing basic and clinical research disciplines. Students will have the opportunity to participate in research projects in a variety of areas including mechanisms of cell damage by reactive oxygen and nitrogen species, biological intervention by antioxidants, chemical damage to DNA and genetic stability, signaling pathways induced as a response to genetic damage, structure-function relationships in mutagenic events, roles of enzymes in influencing damage from chemical agents, and mechanisms of neurological and renal damage induced by metals (especially manganese and mercury).
The primary objective of this program is to provide a meaningful research experience in the field of environmental health sciences to medical students early in their academic careers and encourage more towards careers as physician-scientists. To achieve this objective, the program aims to 1) provide the medical student with the opportunity to conduct mentor-guided research in order to gain an improved understanding of biomedical research and career opportunities in the field; 2) provide students with information about what is involved in a career in biomedical investigation; 3) provide an atmosphere that encourages and facilitates student interaction with a diverse group of established investigators and clinicians in the broad area of environmental health sciences; and, 4) give participants a comprehensive and current overview of environmental health sciences and unsolved research problems in the field.
DESCRIPTION (provided by applicant): Over the last decade, it has become evident that there is a significant correlation between eating a diet rich in fruits and vegetables (foods with high flavonoid content), and a decreased risk for chronic diseases such as cancer. Accordingly, the anti-cancer effects of dietary flavonoids have become an increasing public health interest. Numerous studies in animals and humans have shown that flavonoids are capable of inhibiting carcinogenesis, but the mechanisms by which they act remain largely unknown. Our lab has recently performed a novel biochemical high throughput screen (HTS)in which we identified flavonoids as potent Wnt signal transduction inhibitors. The Wnt pathway is a conserved signaling pathway shown to be important in a number of human cancers. Specifically, abnormal activation of Wnt signaling is present in over 85% of all sporadic cases of colorectal cancer. Given the importance of Wnt signaling in cancer, the possibility that inhibition of the Wnt pathway is one mechanism by which flavonoids exert their anti-cancer effects is especially intriguing. Thus, the main objective of this application is to characterize the role of flavonoids in inhibiting Wnt signal transduction through the following specific aims: 1) By performing structure activity relationship studies of the flavonoid compounds identified in our HTS to determine the structural features required for their Wnt inhibitory activities, and 2) By determining the specific target of our flavonoid compounds in the Wnt pathway. The results of these studies will reveal important information on the mechanism by which an important class of dietary compounds, flavonoids, may inhibit cancer, and may lead to the discovery of novel chemotherapeutic compounds.
Crisp Terms/Key Words: RNA interference, predoctoral investigator, high throughput technology, cadherin, Xenopus oocyte, tissue /cell culture, embryo /fetus, vegetable, fruit, nutrition related tag, cancer prevention, nutrition aspect of cancer, transcription factor, genetic transcription, flavonoid, chemical structure function, biological signal transduction, Xenopus
DESCRIPTION (provided by applicant):
Application is made for continued funding of a long-standing program associated with the Center in Molecular Toxicology at Vanderbilt University. Funds are requested to support eight predoctoral (Ph.D. candidates) and six postdoctoral (already having a Ph.D., M.D., D.V.M., etc.) trainees. The program emphasizes molecular aspects of toxicology and is interdisciplinary. The faculty is drawn from individuals with appointments in Biochemistry, Chemistry, Medicine, Pathology, and Pharmacology, all of whom train postdoctoral fellows. Graduate students in the program obtain degrees through Biochemistry, Chemistry, Pathology, or Pharmacology. Considerable emphasis is placed upon research rotations, the thesis research itself, and participation in seminars, journal clubs, and joint research meetings. There is also much opportunity for learning the operation and application of instrumental systems in research. Graduate students are recruited to the Department of Chemistry through departmental mechanisms, with assistance from the Center. In the other three (biomedical) departments, graduate students are initially recruited into the Interdisciplinary Graduate Program, where they spend the first 9 months in a relatively common core curriculum and do three laboratory rotations.
Graduate students are recruited into Toxicology from these first year pools (the initial year is supported by the institution). Both predoctoral and postdoctoral trainees are selected by the Center's Steering Committee, with guidelines to insure distribution of trainees and monitoring of progress. The list of preceptors includes sixteen faculty, who are all Center investigators. Major research areas in the Center include enzymatic oxidation and conjugation, oxidative damage, DNA damage and mutagenesis, mechanisms of cell signaling, and structural biology relevant to toxicology. Molecular toxicology is recognized as a strong program, and the institution has continued its commitment to making Vanderbilt a leading center for training in this area.
DESCRIPTION (provided by applicant):
This revised ARCH application proposes a project between Meharry Medical College, a historical black college/university (HBCU/MSI), and Vanderbilt University School of Medicine, a research intensive institution (RIU) that focuses on enhancing collaborations between investigators at these institutions in the general area of toxicology. The goal of this proposal is pursue hypothesis-driven research project grant programs in "Molecular Mechanisms of Polycyclic Aromatic Hydrocarbon Toxicity" at MMC in close collaboration with faculty at Vanderbilt University School of Medicine. This arrangement is designed to allow the accomplishment of the following Specific Aims. Specific Aim 1 is to develop the research programs of ARCH faculty as measured by joint, impact publications between MMC-VU research teams by the midpoint of the second year of this initiative. Specific Aim 2 is to develop the research programs of ARCH faculty in a way that fosters the launching of the independent careers of these investigators, as measured by successful acquisition of peer-reviewed funding. The strengths and resources of both institutions have been merged so as to create a joint project that is expected to increase the success rate of research project grant applications by Meharry faculty members to the National Institutes of Environmental Health Sciences (NIEHS). This revised application comprises three main components: 1) the Administrative and Planning Core will be responsible for managing and monitoring the entire project. The administrative core will receive guidance from internal and external advisory committees. 2) The research program development core will consist of three pilot projects and one research project conducted by MMC investigators. The pilot and research projects establish close collaborations between investigators from MMC and Vanderbilt University School of Medicine. 3) A well-integrated facility core is requested to support the ARCH investigators. Over the tenure of the proposed project, these three components will develop into a cohesive program of environmental health science research. The research described in this revised application uses exposure to "B[a]P" as a model to understand the etiology of neurological dysfunction and cancer.
REVIEW OF ADMINISTRATIVE PLANNING CORE
DESCRIPTION (provided by applicant)
The Administrative and Planning core will manage and monitor the progress of this program. Specific objectives for this core will be to provide leadership that will assure the scientific growth and professional development of the MMC investigators; to ensure effective collaboration between MMC scientists and VUMC scientists; to foster an enhanced MMC/VUMC partnership in toxicological training and research by organizing team meetings, seminar series, and relevant workshops, and an annual toxicology symposium; to provide effective management of the ARCH program administratively and fiscally. This core will be directed by Drs Hood, the principal investigator from MMC, and Aschner from VUMC. Both the Internal and External Advisory Committees will offer guidance to the directors of this core. The administrative mechanism that supports this scientific collaboration is straightforward in that the principal investigator is responsible for overall direction of the project while the project leader at the RIU is charged in managing the projects conducted at VUMC. Leadership responsibilities will be shared by the principal investigator at MCC and the RIU leader at VUMC. Operations at the two Institutions will be integrated as a result of the advisory committees, seminars, and other interactive mechanisms.
DESCRIPTION (provided by applicant)
The long-term objective of the Environmental Health and Justice Collaborative (EHJC) is to facilitate and strengthen neighborhood empowerment and leadership, ongoing information exchange, health promotion, and policy improvements in regard to environmental health and justice - with a focus on industrial and commercial chemical contamination - in the Alton Park/Piney Woods (AP/PW) neighborhood of Chattanooga, Tennessee. In order to accomplish this, the EHJC will build on linkages that have already been established over the past five years among UT researchers who have been investigating levels, exposure pathways, and potential health effects of contamination along Chattanooga Creek; neighborhood organizations spearheaded by the Alton Park Development Corporation (APDC); The Southside Community Health Center (SCHC); and Howard School. A community organizer will be hired, through this grant to work with APDC to develop a neighborhood-based model of information exchange called the Neighborhood Environmental College (NEC) to involve the community in emerging research about chemicals in AP/PW, associated health concerns, and decision-making regarding risk reduction strategies. This model will be a venue to build on existing connections with AP/PW residents about basic environmental health and justice issues. Neighborhood youth will be engaged in the technical research, through Project Explore and the proposed NEC, to participate in hands-on training onsite and at the University of Tennessee in Knoxville (UT). An environmental health specialist will be hired to work with the SCHC to conduct a series of health assessments, to be conducted by neighbors and researchers jointly, including door-to-door, workshop, and focus group methods, to enhance baseline information in these areas and as prioritized by neighborhood collaborators. Finally, to ensure sustainability of the knowledge base and remediation strategies created by the EHJC, community leaders will be identified who can organize and educate other AP/PW members about local environmental issues, encourage ongoing leadership development, and be empowered to act collectively to improve environmental health in the AP/PW and other communities.
DESCRIPTION (provided by applicant)
This grant application requests funding for partial support of a series of symposia with the title "Frontiers in Chemical Toxicology". These symposia are part of the program to be presented by the American Chemical Society Division of Chemical Toxicology at the 236th National Meeting and Exposition of the Society in Philadelphia, Pennsylvania on August 17 through 21, 2008. These symposia will provide forums for the presentation of emerging research in key areas of chemical toxicology, including 1) the structural biology of DNA damage as related to repair, with emphasis on base excision repair and nucleotide excision repair, 2) the role of epigenetics in chemical toxicology, 3) emerging issues of nanotoxicity, 4) cytochrome P450 structure, function, and mechanism, and 5) drug safety prediction as related to cytochrome P450 enzyme inhibition and induction, to the chemical community. The contribution of the chemical community to the development of techniques in this arena has increased greatly in recent years, with future growth only limited by lack of cross-talk between the large numbers of disciplines involved in this area of the biomedical sciences, hence the need for this symposium. Highly respected scientists from a variety of disciplines have agreed to present their most recent findings.
|