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Record Count: 40
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DESCRIPTION (provided by applicant): Studies on the mechanisms that detoxify chemicals and protect cells against toxicity, mutagenicity and cancer are highly significant for human health. Two cytosolic proteins [NAD(P)H:quinone oxidoreductase1(NQO1) and NRH:quinone oxidoreductase2 (NQO2)], with the function of quinone detoxification, were cloned. NQO1-/- and NQO2-/- mice were produced using targeted gene disruption. These mice were born and reproduced normal. However, NQO1-/- mice were shown to exhibit altered intracellular redox status and reduction in abdominal adipose tissue, interstitial cystitis of bladder, myelogenous hyperplasia and B cell deficiency in blood. NQO2-/- mice also showed myelogenous hyperplasia and B cell deficiency. NQO1-/- and NQO2-/- mice showed differential response to menadione induced hepatic damage indicating a role of NQO1 in detoxification and NQO2 in activation of menadione. NQO1-/- and NQO2-/- mice also demonstrated increased susceptibility to develop dimethy1 benzanthracene (DMBA) and benzo(a)pyrene (BP) induced skin tumors as compared with the wild type mice. Studies also showed that reduced levels of p53 and decreased apoptosis contributed to myelogenous hyperplasia and increased susceptibility to develop BP-induced skin tumors. NQO1-/- and NQO2-/- mice were cross-bred to generate double knockout mice deficient in both NQO1 and NQO2.
The major goals of this proposal are to investigate the mechanism and in vivo function of NQO1 and NQO2 in protection against interstitial cystitis and leukemia, immune response and autoimmunity, and susceptibility to chemical carcinogenesis. First aim will characterize double knockout mice, determine its sensitivity to menadione induced toxicity and investigate the mechanism of the role of NQO1 in protection against interstitial cystitis. Second aim will investigate the in vivo role and mechanism of the role of NQO1 and NQO2 in radiation and benzene induced leukemia, immune response and autoimmunity. Third aim will elucidate the in vivo role and mechanism of the role of NQO1 and NQO2 in protection against chemical induced skin and internal organ carcinogenesis. To this effect, double knockout mice will be analyzed for accumulation of NAD(P)H/NRH, alterations in intracellular redox status and accumulation of abdominal adipose tissue, myelogenous hyperplasia and menadione induced hepatic damage. Tissues histology will study lesions in various tissues. Wild type, NQO1-/-, NQO2-/- and double knockout mice will be exposed to radiation and benzene to study susceptibility to develop leukemia and to alum-precipitated NP (4-hydroxy-3-nitrophenyl)acetyl conjugated to CGG (chicken ?-globulin) and NP-CGG to study primary and secondary immune response and to collagen to study autoimmunity. Cytogenetic assays will identify chromosomal translocations. Skin and internal organ carcinogenesis models will study susceptibility of double and individual knockout mice to DMBA and BP induced carcinogenesis. Western, immunoprecipitation, microarrays and proteomic assays will elucidate the role of NQO1 and NQO2 in regulation of p53 and apoptosis/growth/differentiation factors in protection against interstitial cystitis, radiation induced leukemia and BP induced skin carcinogenesis
DESCRIPTION (provided by applicant): Manganese is an essential nutrient that can also be toxic, and exposure to environmental manganese can cause neurotoxicity. In spite of its public health importance, little is known regarding manganese homeostasis. The long-term goals of this program are to employ bakers' yeast as a model eukaryote to understand manganese metabolism and toxicity. The current proposal addresses three distinct but related aspects of manganese biology: (Aim 1) the sensing of manganese during manganese stress; (Aim 2) phosphate as a key determinant of manganese toxicity; and (Aim 3) the impact of mitochondrial iron on manganese binding to the anti-oxidant enzyme superoxide dismutase 2 (SOD2). In Aim 1, "manganese stress" is defined as extreme conditions of manganese starvation or manganese toxicity. Preliminary studies indicate that manganese sensing for these two stresses occurs in separate cell compartments, but in both cases, cells respond through post-translational control of a manganese transporter, Smf1p. Proposed studies will test the hypothesis that Smf1p itself is a sensor for manganese and will examine the mechanism by which Smf1p localization and expression are controlled by manganese stress. Regarding Aim 2, high intracellular phosphate was found to cause profound manganese toxicity in yeast, and this toxicity was reversed through chromatin remodeling factors. The possible epigenetic effects will be probed through yeast genetic screens and transcription profiling studies. Additionally, the profile of manganese-phosphate interactions inside the cell that accompany manganese toxicity will be obtained through 31P-NMR and ENDOR spectroscopy with help from expert collaborators. Finally, Aim 3 explores how a specialized pool of mitochondrial iron competes with manganese for binding to SOD2. Molecular genetics experiments will test the hypothesis that this SOD2-reactive iron is derived from the Fe-S biogenesis pathway, and by inhibiting manganese binding to SOD2, it contributes to mitochondrial damage in a disease of iron overload. The nature of SOD2-reactive iron will be evaluated through a colorimetric assay for mitochondrial ferrous iron and through XANES analyses (by our collaborator J. Penner-Hahn) of the metal coordination environment. Such investigations into SOD2-reactive iron will provide important clues as to how SOD2 normally selects manganese. Overall, this multi-disciplinary approach to understanding manganese ion biology should provide novel insight into the homeostasis of a toxic nutrient.
DESCRIPTION (provided by applicant): The major long-term objectives of the proposed research are [1] to test the hypothesis that lead interacts with calcium binding proteins of the C2 and annexin families, and [2] to identify genes and proteins of these calcium-binding families that are regulated following lead exposure of rats. Lead poisoning remains a pervasive problem in the United States, affecting at least 5% of all children. The proposed research is intended to elucidate molecular mechanisms underlying lead toxicity. Previous studies have demonstrated potent interactions between lead and proteins of the C2 domain family (e.g. protein kinase C and synaptotagmin) and annexins. Furthermore, lead exposure of cells has been shown to regulate the expression of genes encoding calcium-binding annexins. The four specific aims of this proposal are [1] to measure the interactions of lead with proteins of the C2 domain and annexin families, in order to determine the possible targets of lead. [2] To measure gene expression in the brain, kidney and liver of lead-exposed rats. This in vivo model may reveal whether lead exposure differentially regulates the expression of genes encoding calcium-binding proteins. [3] To extend gene expression studies to well characterized cell lines (astrocytes, PC12 cells, fibroblasts and normal rat kidney cells). These studies will complement gene expression measurements from the in vivo model. [4] To deposit gene expression data into a publicly accessible database. Together these studies may reveal which calcium binding proteins interact with lead, and which genes encoding calcium-binding proteins are regulated by lead exposure.
Crisp Terms/Key Words: microarray technology, molecular biology information system, synaptotagmin, neurotoxicology, PC12 cell, cell line, northern blotting, annexin, calcium binding protein, in situ hybridization, astrocyte, intermolecular interaction, lead poisoning, liver, kidney, western blotting, gene expression, fibroblast, polymerase chain reaction, hippocampus, frontal lobe /cortex, laboratory rat
DESCRIPTION (provided by applicant): Nuclear transcription factor Nrf2 regulates ARE-mediated expression and coordinated induction of a battery of antioxidant genes. The products of these genes are known to play critical roles in cellular protection against oxidative stress and neoplasia. Recently, we cloned and sequenced a cytosolic inhibitor of Nrf2 designated as INrf2. INrf2 retains Nrf2 in the cytosol. Antioxidants antagonize INrf2 retention of Nrf2. Nrf2 releases from INrf2. Nrf2 translocates in the nucleus, binds to ARE and activate ARE-mediated expression of antioxidant genes. Preliminary studies have shown that INrf2 is phosphorylated at S104 and that mutant INrf2S104A failed to significantly repress ARE-mediated gene expression as observed with wild type INrf2. The studies have also shown that INrf2 gene is ubiquitously expressed, down regulated in hepatoma cells and induced in response to antioxidants.
The goals of this proposal are: 1) elucidate the role of phosphorylation/dephosphorylation and/or redox modification of INrf2 in homodimerization of INrf2, Nrf2 degradation in basic conditions and antioxidant-induced release of Nrf2; 2) generate conditional knockout mice that do not express INrf2 in liver and epidermis of skin and investigate in vivo roles of INrf2 in Nrf2 signaling and susceptibility to carcinogens; and 3) characterize the cis-elements and trans-acting factors that regulate basal expression, down regulation of INrf2 in hepatoma cells and induction in response to antioxidants. To this end, we will use transfection, orthophosphate labeling, immunoprecipitation and Western analysis along with inhibitors of phosphorylation and phospho-specific antibodies and redox modulators. This will determine if INrf2 is phosphorylated/dephosphorylated and/or redox modulated in basic conditions and in response to antioxidants that leads to homodimerization and/or Nrf2 degradation and/or release of Nrf2 from INrf2. Mass spectrophotometry will be used to precisely map the modified sites in INrf2. We will use Cre-Lox system to delete exon 2-4 from endogenous INrf2 gene in mouse models. This will generate conditional knockout mice that do not express the INrf2 gene in liver and epidermis of skin. These will be analyzed for the role of INrf2 in Nrf2 signaling and their susceptibility to benzo(a)pyrene induced skin and liver tumors as compared to wild type mice. PCR will be used to construct INrf2 deletions, internal deletions and mutations, including Oct-1, c/EBP and ARE elements. The transfection and band/super shift assays will be used to identify the cis-elements and trans-acting factors that control the down regulation of INrf2 gene in hepatic tumor cells and antioxidant induction.
DESCRIPTION (provided by applicant):
This proposal brings together investigators with a long track record in studying epigenetic gene silencing, and associated promoter DNA hypermethylation, in cancer to study the interaction of these events with key environmental exposures which foster cancer risk. The intent is to test, using a unique animal model, the hypothesis that a critical key to how environmental factors increase cancer risk is by modulating and/or inducing heritable epigenetic gene silencing events which allow cells to survive stress and, thus, engage in the early clonal expansion from which cancers arise. To study this, the intent of this initiative is to utilize Hic1 mice which develop gender specific, and age related, epithelial (lung, Gl, liver, etc), soft tissue, and lymphoid tumors based on there being one allele step away from an epigenetic gene silencing event. HIC1 is a gene frequently epigenetically silenced in human cancers. In all cases, the remaining wild type Hid allele, in tumors from the Hic1 mice, is transcriptionally silenced in association with promoter DNA hypermethylation. The gene encodes a transcriptional represser for SIRT1, a key sensor of cell stress, mediator of survival, and regulator of p53. Hid deficient mouse and human tumor cells have increased SIRT1 with resultant diminished p53 function and defective apoptosis response to DNA damage. Intriguingly, SIRT1 is, itself, a chromatin modifying protein which has recently been found to participate in the aberrant silencing of cancer genes. This initiative will thus test how this novel network of epigenetic abnormalities may be induced and/or modulated by important environmental factors, such as dietary folate levels, carcinogen exposure (NNK and PhIP), and inflammatory responses to allow cells to abnormally survive stress and become at risk for cancer. For all tested environmental events, incidence and rates of tumor development in Hic 1 vs. mice will be mapped and matched with the sequence of changes in Hic 1 methylation and expression status, levels of SIRT1, and the methylation and expression status of key cancer genes. These studies should provide, in terms of public health, documentation that the earliest key steps for risk of important cancers may involve heritable, and potentially reversible, epigenetic events. These, in turn, may be driven, and/or modulated, by key environmental factors. Thus, it is inferred that a key to cancer prevention may be to induce reversal of, or block, epigenetic gene silencing.
DESCRIPTION (provided by applicant): This grant, first, emphasizes discovering aberrantly silenced and DNA hypermethylated colon cancer genes and defining their function in colon cancer progression. A second emphasis is to dissect the chromatin alterations which may initiate and/or maintain this gene silencing with the translational goal of better understanding colon cancer risk and fostering new prevention and treatment strategies. The first goal involves a microarray approach, based on blocking chromatin events associated with abnormal cancer gene silencing, to screen for the hypermethylated genes. This, already, has facilitated discovery of important genes and we will now improve the sensitivity to facilitate total genomic coverage including using new findings from studies outlined below. For the second emphasis, we study HCT116 cells genetically deleted for DNA methyltransferases (DNMT's) to determine how these enzymes co-operate to establish and/or maintain, promoter DNA hypermethylation and gene silencing. Such studies and siRNA studies of other cell lines reveal that colon cancer cells are surprisingly independent from the major "maintenance" DNA methyltransferase (DNMT), DNMT1, for sustaining gene hypermethylation and silencing. This enzyme plus DNMTSb must be deleted to abolish virtually all total and promoter specific DNA methylation and cause re- expression of aberrantly silenced genes. We are replacing DNMT's in such cells to establish gene re- methylation models and then identify how DNMT's are complexed and targeted to genes. We have recently determined that the class III HDAC, SIRT1, helps maintain the silencing of the aberrantly silenced genes. Drug induced, dominant negative mediated, and SiRNA blocks of SIRT1 function all induce these genes to re-express without any loss of DNA methylation and synergize with DNA demethylation class I and II HDAC inhibitors to do so. SIRT1, mediates cellular response to environment, nutrient status, and stress, and increases longevity of lower organism and mammalian cells thus providing an important potential link between aging, gene hypermethylation, and cancer. We will determine whether SIRT1 contributes to initiation of aberrant DNA methylation and how it participates in the silencing of cancer genes by determining specific molecular interactions with other chromatin components of gene silencing. Relevance to Public Health: Our studies then provide, in terms of public health, discovering better means to understand and predict the risk of colon cancer. Our findings are suggesting new means, by reactivating abnormally silenced genes, for constructing prevention and treatment strategies for this disease. This proposal seeks to identify genes that are silenced by aberrant methylation and that contribute to the tumorigenic phenotype of colon cancer, and to characterize the mechanisms by which the DNMTS and HDACs function to control gene silencing in colon tumor formation. Strengths of the work include the expertise of the investigator, the reagents already generated, and exciting discoveries made during the last funding period. Weaknesses include the descriptive nature of the work, although the addition/improvement of aim three begins to address this.
DESCRIPTION (provided by applicant):
Epigenetic mechanisms such as methylation may be very important in human disease, especially for diseases of older ages. Yet studies documenting epigenetic changes over the human lifespan, the vulnerability of epigenetic marks to environmental exposures, and the subsequent effects on human disease have been limited due to the absence of technical and biosample resources. A team has been assembled with the technology and resources to measure changes in methylation over time in the same individual for the purpose of examining a relationship between exposure and such changes, and assess the relationship between methylation and disease, by combining the epigenetic and epidemiologic expertise at Johns Hopkins with the resources of colleagues at the Icelandic Heart Association (IHA). The IHA has followed over 18K participants of the Reykjavik Heart Study since 1967 and has recently collected extensive cardiovascular and functional measures on 5758 of the surviving cohort as part of the AGES-Reykjavik study. Of these, 638 participants have DNA samples available for epigenetic measurement from two visits spanning 15 years, allowing for measurement of epigenetic changes over time in the same individual, which must occur if environment can influence epigenetic marks, but has never been directly observed in a human population. In addition, diet and smoking data and serum samples are available since 1967 as well as recent phenotype measures and disease outcomes for all 5758 AGES participants (2004-2005). The specific aims include assessing the: (1) Impact of environmental factors including dietary fish intake, serum folate levels, and smoking on inter-individual changes in whole-genome and candidate-gene specific methylation spanning 15 years; (2) Relationship between 15-year changes in methylation and subsequent disease-related quantitative measurements such as blood pressure, BMI, central adiposity, and coronary calcification; (3) Cross-sectional relationship between urinary cadmium (Cd) and candidate gene methylation; and (4) Cross-sectional relationship between candidate gene methylation and disease outcomes including CVD and cancer. This unique resource and team allows the first opportunity for longitudinal epigenetic measurement over 15 years in the same people, and connection of these epigenetic measurements to dietary and smoking exposures, as well as to cancer and cardiovascular disease consequences.
DESCRIPTION (provided by applicant): Domoic Acid (DA) is a naturally occuring marine toxin that is responsible for Amnestic Shellfish Poisoning (ASP), or even death in humans who consume tainted shellfish. Within the past decade, rising levels of DA on the US west coast has been responsible for outbreaks of toxicity affecting fish, shellfish, shorebirds and sealions. The highest levels of DA ever recorded in the United States (exceeding established safety levels of 20 ppm by more than 280 ppm) were found in harvesting beaches of several subsistence level Native American Tribes within the past four years. The purpose of this five year longitudinal cohort study of 625 Native Americans is to determine the incidence and prevalence of domoic acid related illness in this at-risk group and to identify both exposure and host factors associated with the occurrence of illness, including the effects of repeated "low" level exposure. Participants will be randomly selected from four US and one Canadian Tribe and will represent five at-risk age groups: infants, young children, older children, adults and geriatric. They will have varying levels of exposure and will be studied annually with standard, age-appropriate neuropsychological measures of memory and cognition. Exposure will be uniformly determined through 1) bi-monthly shellfish sampling and standard detection measures for DA conducted by NOAA from June to October of each year and 2) standardized dietary and shellfish consumption intake measurement. The study design will also enable us to determine the percent of the population with one or more risk factors, examine threshold levels of exposure for five different age groups, re-examine current FDA established safety levels for different age groups, and study the impact of early exposure on child development. Our ultimate goal is to provide a rational basis for shellfish regulation and preventive education to disproportionately exposed and medically underserved Native American communities.
DESCRIPTION (provided by applicant): The aflatoxins are a paradigm among mycotoxins and occupy a central place in environmental toxicology. Hepatocarcinomas are the third most common cause of cancer death in the world. Hepatitis infections and dietary aflatoxin are major risk factors contributing to the incidence of this disease. The aflatoxigenic Aspergillus species, A. parasticus, A. flavus and A. nomius, commonly infect grains and food stuffs where clear epidemiological data correlate to human disease. Chronic ingestion is a major cause of premature death in Asia, Africa and Central America. A direct link has been forged between the interaction of the metabolically activated form of the toxin and DNA, particularly in a hot spot in the p53 gene leading to mutation of its important encoded cell cycle regulating protein. Understanding its biosynthesis will lead to control of this environmental carcinogen. The aflatoxins are created by an unusually long and complex biosynthesis. Key molecular rearrangements, some remarkable mechanistically, are catalyzed by cytochromes P450. The mechanisms of these cleavage and rearrangement reactions will be studied and modeled by chemical mimetics to understand their underlying chemistry. The second, and principal, goal is to capitalize upon exciting progress made in the current grant period to understand the function of non-reducing iterative polyketide synthases central to aflatoxin biosynthesis and many other fungal natural products. Of the three principal types of PKSs, least is known about the programming of iterative Type I systems; that is, how are starter units recruited and synthesis begun, how is chain length determined, how is the canonical and intrinsically reactive poly 2-keto intermediate stabilized, how is redox state controlled during chain elongation, and, finally, how are intramolecular cyclizations controlled to specific ring forms in preference to others. Superimposed on this is the fundamental question of iterative catalysis, a rare but impressively efficient process in which active sites in these polydomainal enzymes are used over and over again, accommodating a sequence of growing substrates yet faithfully executing a synthetic program. We have discovered two previously unrecognized domains in these domains we now believe are general to this class of enzymes, a starter unit:acyl-carrier protein transacylase (SAT) domain, which might account for the classical observation of a starter unit effect, and a product template (PT) domain, which in preliminary results clearly has a role in polyketide stabilization and product templating. Biochemical, X-ray crystallographic and mass spectrometric experiments are outlined to understand the functions of these domains individually and working together in what is already emerging as a new picture of iterative catalysis.
PUBLIC HEALTH RELEVANCE The aflatoxins occupy a central place in environmental toxicology. Hepatitis infections and dietary aflatoxin from infected grains and foodstuffs are major risk factors for hepatocarcinoma, the third most common cause of cancer death in the world. Understanding its biosynthesis will lead to its control.
DESCRIPTION (provided by applicant):
Human health risks associated with the presence of chemicals in sediments arise from either direct contact with the sediments or by eating fish and shellfish that have accumulated chemicals from the sediments. Emerging laboratory-scale research by our group and others has shown that contaminant transport pathways and bioavailability can be interrupted by modifying and enhancing the binding and contaminant assimilation capacity of natural sediments. This is achieved by adding sorbent amendments such as activated carbon for binding persistent organic pollutants and natural minerals such as apatite, zeolites, or bauxite for the binding of toxic metals in sediments. Critical barriers in the adoption of this in-situ remediation approach is the availability of efficient delivery methods for amendments to impacted sediments and understanding of physical and biological processes in field sites that control technology effectiveness. The main aim of this research project is to develop the in-situ remediation technology through a pilot-scale investigation aimed at addressing the critical barriers in the advancement of the technology. This field research project will be carried out at two PCB/DDT-impacted sensitive wetland sites. The research design will involve application of the technology in a quarter acre plot in each site and a monitoring plan to understand how the fate and transport processes of PCB/DDT in the wetland environment is impacted by the application of the sorbent amendments. Biological monitoring will include PCB/DDT bio-uptake measurements in a freshwater oligochaete carried out in field exposure chambers and also in laboratory microcosms. The physicochemical monitoring will include aqueous partitioning and desorption rate from sediment, two measures that define the bioavailability processes of sediment bound contaminants. The PCB/DDT fate and transport process understanding will be used to assess human health risk benefit from the technology based on a dermal uptake model and a food-chain model. Sediment-bound contaminants such as PCBs and DDT pose a public health risk through contamination of the food chain and through direct exposure. This field research will evaluate the effectiveness of a novel approach to alter the binding capacity of sediments to reduce human exposure to such contaminants.
Description (provided by applicant): The goals and responsibilities of the Administrative Core for the Center in Urban Environmental Health include: 1) To provide the administrative infrastructure to support the coordination and integration of the research goals, Facility Cores, pilot projects and outreach activities in the Center. 2) To provide the administrative infrastructure to support the enrichment of the intellectual environment at the Johns Hopkins University in the environmental health sciences through seminar programs, focused research retreats and the recruitment of outstanding students and faculty. 3) To coordinate the administrative activities of this Center with those of other NIEHS funded Core Centers and the leadership at the National Institute of Environmental Health Sciences.
DESCRIPTION (provided by applicant): The main objective of this project is to test the hypothesis that exposure to metals in children will affect their cardiovascular risk and may predispose them to cardiovascular disease. It is based upon a growing epidemiological literature, by us and others, indicating that exposure to lead, cadmium, or arsenic increases cardiovascular risk. However, most studies of the impact of metals on cardiovascular risk have been carried out in adults, and the susceptibility of children to the cardiovascular effects of metals is largely unknown. Primary hypotheses: 1) Exposures to lead, cadmium, or arsenic are positively associated with blood pressure levels in children; 2) Exposures to lead, cadmium, or arsenic, are positively associated with serological markers of inflammation and endothelial dysfunction (C-reactive protein [CRP], interleukin-6 [IL-6], intercellular adhesion molecule-1 [ICAM-1], and tumor necrosis factor alpha [TNF-alpha]) in children; and 3) Exposures, cadmium, or arsenic are inversely associated with heart rate variability in children. Design and setting: We propose to conduct a cross sectional epidemiological study of the association between exposure to lead, cadmium, or arsenic and markers of cardiovascular risk in children residing in the Torresn metropolitan area, Mexico. We will contact the children who participated in the Torresn Study of Lead and Neurocognitive Function in 2001, when they were 6 - 7 years old. We expect to recruit 512 (85%) of the original study participants, who will be 14 - 15 years old at the time of field work for the present study in 2009. This population offers a unique opportunity to evaluate the cardiovascular effects of metals in a large and well characterized group of children whose lead exposure has been previously studied. In the present study, we will obtain two measurements of metal exposure two months apart (lead in whole blood and cadmium and arsenic in urine) and evaluate their association with cardiovascular risk markers. The primary outcomes will be blood pressure, serological markers of inflammation and endothelial dysfunction (CRP, IL-6, ICAM-1, and TNF- alpha), and heart rate variability. Other endpoints will also be assessed, including markers of renal proximal tubular injury, cardiometabolic abnormalities (insulin resistance and lipid levels), and neurotoxic endpoints. Significance: Children in Torresn are exposed to lead, cadmium, and arsenic from dusts generated by the Met-Mex Peqoles smelter, the largest lead smelter operating in the Americas. While the average exposure to metals in this population is high, the range of exposure overlaps with that of children in US and in other Western countries. The current population thus represents an efficient way to obtain information on the impact of a wide range of metal exposure at the population level. The information obtained from children in Torresn will be relevant not only to local area residents, but to many children in the US and abroad. PUBLIC HEALTH RELEVANCE: The main objective of this project is to test the hypothesis that exposure to metals in children will affect their cardiovascular risk and may predispose them to later cardiovascular disease. We propose to conduct a cross- sectional epidemiological study of the association between exposure to lead, cadmium, or arsenic and markers of cardiovascular risk in children residing in the Torresn metropolitan area, Mexico. Almost all studies of the impact of metals on cardiovascular risk have been carried out in adults, and the susceptibility of children to the cardiovascular effects of metals is largely unknown. The information obtained in this study will be relevant to millions of children in the US and abroad who are chronically exposed to lead, cadmium, and arsenic in the environment.
DESCRIPTION (provided by applicant): Background: The cardiovascular consequences of long-term exposure to low concentrations of mercury or arsenic are insufficiently understood. Mercury has been linked to cardiovascular risk in some, but not all, studies, and its association with the progression of atherosclerosis is uncertain. High arsenic exposure is an established cause of vascular disease, but the effect of low concentrations, more typical of the exposure of the US population, is essentially unknown. Since fish intake is the main source of methylmercury exposure in the general population, and a major source of organic arsenic compounds, the effects of these compounds may be confounded by the cardioprotective n-3 fatty acids in fish. Objective: To investigate the association of mercury and arsenic exposure with carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, in a cohort of individuals followed during 1989-99. Hypothesis: Exposure to mercury or arsenic, as determined in toenails, are associated with baseline carotid IMT and with its progression over 10 years follow-up. These associations are independent of established coronary risk factors and of plasma phospholipid long-chain n-3 fatty acids, a biomarker of fish oil intake. Setting: Cohort of 2,085 men and women, aged 45 years and older and residents in Washington County, MD, who participated simultaneously in the CLUE II cohort (that collected toenail clippings) and either in ARIC or in the CHS cohorts (that measured IMT and cardiovascular risk factors). Design and measurements: Prospective longitudinal study of the association of baseline mercury and arsenic levels with carotid IMT progression over 10 years. Toenail mercury and arsenic will be measured by instrumental neutron activation analysis, and plasma n-3 fatty acids by capillary gas chromatography. Carotid IMT has already been measured by B-mode ultrasound. Statistical analysis plan: Longitudinal data analysis methods will be used to model IMT progression. Important statistical issues will be the control of measurement error in repeated IMT measurements, the control of the effect of cardiovascular risk factors on IMT progression, and the evaluation of the joint effect of mercury or arsenic and n-3 fatty acids. Relevance: Confirmation of the role of mercury or arsenic on atherogenesis could impact current environmental and dietary public health recommendations.
Crisp Terms/Key Words: cardiovascular disorder risk, environmental exposure, clinical research, longitudinal human study, ultrasonography, nutrition related tag, diet, mercury poisoning, arsenic, human subject, cardiotoxin, omega 3 fatty acid, activation analysis, carotid artery, cardiovascular disorder epidemiology, atherosclerosis, fish
DESCRIPTION (provided by applicant): Human populations are exposed to multiple chemicals through all environmental media. Environmental policies are fragmented and were designed primarily to control exposures to single chemicals in a single medium. Information on low-level population exposure to multiple chemicals has been limited until recent years of the National Health and Nutrition Examination Survey. Epidemiological data on the health effects of chemical mixtures is urgently needed to interpret the health implications of actual environmental exposures. We propose to determine whether concurrent exposure to a mixture of nephrotoxic metals is associated with clinical measures of kidney disease. Our long-term goal is to advance our understanding of the health effects of mixtures and improve the scientific basis for environmental policy. We will examine metal mixture exposures in a representative sample of the US population. The metals are barium, cadmium, cobalt, lead, mercury, molybdenum, and uranium. These metals were selected on the basis of toxicological or epidemiological evidence of nephrotoxicity and known population exposure. Demographics and socio-economic characteristics of the exposed population will be described. We will test the hypothesis that multiple exposures are distributed differently across race/ethnicity or socio-economic status. A mixture exposure metric will be developed that accounts for differences in each metal's nephrotoxic potency. Nephrotoxic potency will be determined from research literature. We will examine 2 additional hypotheses: (1) the toxicity-weighted mixture exposure metric will reveal exposure disparities by race/ethnicity or socio- economic status; and (2) those with higher mixture exposure metrics will have reduced creatinine clearance and estimated glomerular filtration rates and increased urinary albumin-creatinine ratios. We will test our hypotheses using contingency table analysis, analysis of covariance, and multivariate regression. The significance of this project is three-fold. First, characterization of mixture exposure in the US population is a unique contribution of this project. Second, the burden of kidney disease falls disproportionately on minority and poor populations perhaps due to differential exposure to metal mixtures. Third, this research demonstrates the proposed exposure assessment design in individual-level epidemiological research. Environmental policies rest primarily on studies of single chemical exposure while actual exposures are to mixtures. This research addresses whether current environmental policies protect public health. The National Institute for Environmental Health Sciences stated in its 2006-2011 Strategic Plan that maximal public health impact depends on conducting research relevant to societal decision making.
DESCRIPTION (provided by applicant): End stage renal disease (ESRD) is associated with substantial morbidity and mortality. Strategies to prevent the renal function decline that can ultimately result in ESRD are essential. The impact of environmental exposures has received relatively little attention in this regard, despite the fact that exposures such as cadmium and lead are known renal toxicants that are stored long-term in the body and ubiquitous in humans. In fact, the lead and cadmium dose-effect curves for renal function remain uncertain for the low to moderate range of doses. The proposed study will investigate a broad set of causes of renal function decline, including lead, cadmium, blood pressure, diabetes, nephrotoxic medication use, genetic polymorphisms, and age. This application is a competing renewal application of the study "Exposure, dose, body burden, and health effects of lead" (Schwartz BS, PI) conducted from 1997-2001. It will build on data, from the large cohort of current and former lead workers and participants without occupational lead exposure in the originally funded grant. Study subjects have a wide range of lead exposure and dose measures and renal outcome data from three visits each over an average of 2.2 years. Analysis of existing data has already provided very important results, including longitudinal decline in renal function associated with lead dose measures; interaction between age and lead dose on renal function and renal function decline; interaction between ALAD genotype and lead dose on renal function; and associations of environmental level cadmium dose with elevated NAG in a subset of lead workers.
However, in order to better understand the causes of renal function decline, cadmium dose must be characterized in all subjects, additional genotypes must be measured, and additional follow-up time is needed because of the slow rate of renal function decline. We propose to include 675 participants from the first study and enroll 225 new current or former lead workers over age 45 years, those at greater risk for renal function decline. We will obtain blood and tibia lead, genotyping, urinary cadmium, BUN, serum creatinine, measured and calculated creatinine clearances, NAG and RBP during 3 evaluations at yearly intervals. The specific aims are to determine: 1) if lead and cadmium dose are or continue to be associated with renal function at cross-section and longitudinally; 2) if there is effect modification by lead or cadmium dose, respectively, on associations between cadmium or lead dose and renal function decline; 3) if hypertension modifies the relations of lead or cadmium dose with renal function decline; and 4) whether polymorphisms in the genes for ALAD, VDR, ACE, and eNOS modify or continue to modify relations of lead and/or cadmium dose with renal outcomes. We believe the proposed work will allow a more complete understanding of the causes of renal function decline and lead to the development of public health interventions to prevent this considerable public health problem.
Crisp Terms/Key Words: hypertension, urinalysis, genetic polymorphism, human subject, chronic renal failure, renal toxin, cadmium, lead, metal poisoning, lead poisoning, occupational health /safety, epidemiology, longitudinal human study, bone imaging /visualization /scanning, Asian, environmental toxicology, gene environment interaction, clinical research, environmental exposure
DESCRIPTION (provided by applicant):
Hepatocellular carcinoma (HCC) is a major cause of cancer morbidity and mortality in many parts of Asia, including China and Thailand, and in sub-Saharan Africa, where there are upwards of 600,000 new cases and deaths each year. The impact of HCC is exacerbated by a median age of diagnosis of between 45 and 50 years and it is nearly always fatal. The major known etiological factors associated with development of HCC in these regions are infection with hepatitis B (HBV) and/or hepatitis C (HCV) virus and lifetime exposure to high levels of aflatoxin B1 (AFB1) in the diet. HCC is also the most rapidly rising solid tumor in the US and is overrepresented in minority communities. While knowledge of the etiology of HCC has spurred many mechanistic studies to understand the pathogenesis of this disease, this information is only just beginning to be translated into development of preventive and clinical interventions in high risk populations. The goals of this project are to develop and validate biomarkers reflecting the biological effects of exposures to chemical and viral toxicants in the etiology of liver cancer. In all chronic human diseases, including cancer, ambient exposures to multiple environmental agents are significant contributors. The specific aims of this project are: 1) To develop quantitative mass spectrometric methodologies for analysis of all the major excreted aflatoxin metabolites; 2) To determine the power of HBV mutation serum prevalence and aflatoxin-specific p53 mutation serum concentration in predicting cancer outcome and disease risk in cohorts in rural China and West Africa; and 3) To continue to extend our observations on the multipartite roles that aflatoxin, HBV and HCV, an emerging infection, play in the development of HCC in a cohort in Northern Thailand. It is our hypothesis that combined use of biologically effective dose biomarkers, susceptibility biomarkers and genetic biomarkers will reveal the sub-set of high-risk people within the population who would benefit from targeted intervention.
DESCRIPTION (provided by applicant): Human exposure to anthropogenic or naturally occurring chemicals contributes to the incidence of neurological disease. To estimate and minimize the human risk of neurological disease from chemical exposure, it is important to identify whether specific chemicals, or classes of chemicals, produce neurotoxicity. Biomarkers of neurotoxicity permit evaluation of exposure to an agent (i.e., dose) and the vulnerability of specific brain structures and cell populations, such as neurons and glial cells, to damage (i.e., effect). A useful approach to assess neurotoxicity is to identify marker proteins of neuronal or glial origin that are sensitive to change as a result of neurotoxic insult. Our approach to the development of a biomarker of neurotoxicity focuses on the peripheral benzodiazepine receptor (PBR), a glia-specific protein. The rationale for this strategy is that reactive gliosis is the earliest and most widespread response of the nervous system to injury. Quantification of a widespread response is needed as a generic biomarker when there is a paucity of knowledge about neuronal targets that may be damaged by a specific chemical. Although the PBR has now been used extensively by us and others as a biomarker of neurotoxicity in the adult brain, it has never been tested in the developing brain. Thus, the specific aims of this proposal are: (1) apply the PBR as a biomarker of neurotoxicity in developing animals; (2) to continue the application of the PBR as an in vivo biomarker of neurotoxicity using small animal imaging; and (3) to determine if the pharmacological activation of the PBR can prevent damage and/or promote recovery from chemical-induced brain injury. A novel aspect of the proposed work is the use of the PBR as an in vivo biomarker of neurotoxicity using state-of-the-art small animal brain imaging techniques. To the best of our knowledge, this is the first validation of a biomarker of neurotoxicity that will permit the study of the living brain in small animals following environmentally-relevant exposures to neurotoxicants. The validation of this technology may serve as a first- tier screening method in neurotoxicity testing of chemicals. Lastly, emerging evidence suggests that the pharmacological activation of the PBR may have neuroprotective effects. We will test this hypothesis in an animal model of demyelination. These studies may have important implications in the development of a novel therapeutic strategy for the treatment of brain injury.
DESCRIPTION (provided by applicant): The overall goal of this project is to establish the usefulness of magnetic resonance microimaging as a tool to study myelination toxicology and apply it to investigate hypomyelination caused by lead poisoning. Myelination is a very complex process; myelination starts at the different time point with different rates for each white matter tract. As a result, comprehensive characterization of myelination status, even of the normal state, is not a straightforward task. This poses a great challenge for toxicological assessment of myelination. In this project, we will use the ex vivo high-resolution MRI and a rat neonate model to characterize the temporal and spatial profile of the myelination process. Using this technique following three aims will be pursued.
Aim 1: Characterization of temporal and spatial profile of the normal rat myelination process using MRI and fixed brain samples. Hypothesis: "Ex vivo high-resolution MRI can reveal the dynamic process of myelination three-dimensionally in a tract-by-tract basis". The microimaging technique will be applied to a series of normal brain samples at different development stages to monitor the myelination process. The observed changes of MR parameters will be correlated with histology to confirm the hypothesis.
Aim 2: Study of the myelination abnormality by high-dose lead administration. Hypothesis: "Ex vivo high-resolution MRI can sensitively and efficiently detect myelination abnormalities" Hypomyelination by lead uptake has been previously reported and our preliminary data show that MRI can sensitively detect the hypomyelination of specific white matter tracts. We will use this system to compare MRI findings and histology data and to validate the hypothesis.
Aim 3: Study of the temporal, spatial, and dose profiles of the myelination abnormality by low-dose lead administration. Hypothesis: "Low-dose lead uptake induces the myelination abnormality, which is independent of malnutrition". Hypomyelination by lead uptake has been considered as one of the important developmental impairments by the lead uptake. However, to date, it has not been clear whether the observed hypomyelination is secondary to the concomitant malnutrition and weight loss. Using the MRI-based technique and normative database established under Aim 1 and 2, we will perform comprehensive myelination studies to examine the hypothesis
Crisp Terms/Key Words: newborn animal, laboratory rat, histology, lead poisoning, myelinopathy, myelination, developmental neurobiology, neurotoxin, magnetic resonance imaging, electron microscopy, neurotoxicology, three dimensional imaging /topography
DESCRIPTION (provided by applicant): Despite significant efforts during the last three decades to reduce lead contamination of the environment, a significant number of children continue to be exposed to this potent and ubiquitous neurotoxicant. A recent report by the Surgeon General of the United States (Satcher, 2000) indicates that "lead poisoning poses one of the greatest environmental threats to children in America". It further states that the latest data show that in the United States, 1 in 20 children under the age of 6 have blood lead levels exceeding those considered to produce lasting deficits in cognitive function. Unfortunately, this problem is not going to disappear in the near future and we must devise new strategies to ameliorate or modify the devastating effects of lead on the central nervous system. The goal of the work proposed is to continue to elucidate the molecular mechanisms of lead-induced neurotoxicity. Our work has demonstrated that the N-methyI-D-Aspartate (NMDA)-type of glutamate excitatory amino acid receptors is a target for lead in the central nervous system. This is important because NMDA receptor function is essential for a number of physiological processes in the developing and mature brain. One of these processes is the acquisition and consolidation of learning and memory. We have shown that exposure to lead during development produces lasting changes in learning and memory in a rodent model of lead neurotoxicity. Further, the impairment in learning is associated with deficits in long-term potentiation in the hippocampus and alterations in NMDA receptor subunit genes and protein expression. Based on this new knowledge, we tested the hypothesis that environmental enrichment may alter the cognitive and molecular deficits induced by lead. Our studies show that environmental enrichment is able to reverse the cognitive and NMDA receptor deficits induced by developmental exposure to lead. This is an extremely important finding because it demonstrates that some of the lead-induced cognitive and molecular deficits are reversible. Further, environmental enrichment is an intervention that is applicable to children. The goal of our proposed studies is to further our understanding of the neurobiological substrates associated with lead-induced neurotoxicity and its reversibility by environmental enrichment. It is important to determine whether environmental enrichment is an intervention strategy that benefits children of any age and if the benefits are long lasting.
Crisp Terms/Key Words: environmental exposure, cAMP response element binding protein, neurotoxicology, gel mobility shift assay, SDS polyacrylamide gel electrophoresis, long term potentiation, NMDA receptor, receptor expression, receptor binding, memory, learning, cognition, protein structure function, in situ hybridization, neurotoxin, developmental neurobiology, lead poisoning, immunocytochemistry, electrophysiology, hippocampus, laboratory rat
DESCRIPTION (provided by investigator): The overall goal of this research is to test the hypothesis that there are differences in response to the immunotoxic effects of mercury compounds in humans, and that susceptibility determinants are enriched in families with cases of autism/autism spectrum disorders (ASD). This research is relevant to understanding preventable risk factors for autism/ASD, based upon the hypothesis that mercury compounds by themselves do not cause autism/ASD but may contribute to the risks of autism/ASD through their immunotoxic properties, in combination with genetic susceptibility and co-exposures to other risks, such as infections. Based upon extensive findings of genetically determined susceptibility to mercury immunotoxicity in rats and mice, we hypothesize that there is a range of susceptibility for mercury-induced immunotoxicity in human populations. We specifically hypothesize, based upon the experimental literature by us and others, that individuals within families with multiple cases of autism/ASD, will have heightened responsiveness to the immunotoxic effects of mercury compounds. The eventual goal of this research is to identify candidate genes that influence individual responsiveness to the immunotoxic effects of mercury compounds. In order to accomplish this goal there is a primary need to define the phenotype of mercury-induced immunotoxicity, which is the goal of this project. We will test in vitro responsiveness to mercury in PBMCs obtained from volunteers. Responses will be measured by FACS analysis of cell surface markers and by ELISA measurements of released cytokines. A dose-response curve will be carried out, in vitro, in order to determine the slope for each individual. Replicability will be assessed by repeat measures of the same individuals; method validation will be completed by analysis of a new set of individuals. The overall relevance of the in vitro system will first be tested by comparing PBMCs from men and women (cycling, in the luteal phase). In the second phase, we will test the hypothesis that patients with autism are more susceptible to mercury-induced immunotoxicity by comparing in vitro responses of PBMCs among family trios (autism cases plus parents) with unrelated controls. Accomplishing the goals of this project will be the first stage in developing a broader study of gene-environment interactions in autism, as well as a targeted search for candidate genes related to mercury susceptibility in humans.
DESCRIPTION (provided by applicant): Childhood lead poisoning persists as a major public health problem throughout the world, despite efforts to reduce lead hazards in the environment. Childhood exposure to low-level lead can permanently reduce intelligence, but the neurobiologic mechanism for this effect is unknown. The vulnerability of the developing brain to lead toxicity is maximal during the peak of synaptogenesis and activity-dependent cortical plasticity. This project utilizes a well-characterized animal model of cortical development, the rodent barrel field, to evaluate the effects of lead on the development and activity-dependent refinement of cortical circuitry. The barrel field of rodent somatosensory cortex contains a map of the whisker pad in which discrete clusters of neurons, called barrels, receive input from individual whiskers. This topographic map develops postnatally, and experimental manipulations such as whisker removal during a critical period in the first postnatal week modify the structure and topographic map of the barrel field. Preliminary studies have shown that neonatal lead exposure impairs the development of columnar processing units in immature barrel cortex. Lead also decreases the plastic response to follicle ablation in the barrel field model of activity-dependent cortical plasticity. Lead can directly alter glutamatergic neurotransmission and interfere with downstream signaling pathways that coordinate gene expression. We hypothesize that lead impairs the development of cortical columns by altering CREB phosphorylation and the expression of genes that are known to play a role in development and plasticity. The aims are: 1) to determine whether lead-induced changes in barrel size are caused by reduction in barrel field axonal and dendritic arbors or neuronal number, 2) to determine whether the effects of lead can be blocked by the NMDA antagonist dextromethorphan, inhibition of Ras with FPT III, or inhibition of PDE4 with rolipram, 3) to determine whether postnatal lead exposure increases or decreases phosphorylation of CREB, ERK1/2 or CaMKIV in the developing barrel field, 4) to determine whether lead exposure alters basal or inducible expression of the transcription factor Egr1, the growth factor BDNF, orsynapsin I and II in the developing barrel field; 5) to determine the effect of lead exposure on Egr1, BDNF, synapsin I and GAP-43 expression after neonatal follicle ablation.
DESCRIPTION (provided by applicant): The goals of our research program are to determine which interventions are most effective at reducing the burden of mortality and morbidity among women and children in high-risk populations in developing countries. At our field site in southern Nepal, acute respiratory illness (ARI) has been a leading cause of mortality among young children. Besides immunization there is little evidence for effective primary preventive approaches for ARI on a population basis. Low birth weight is highly prevalent in this population as well affecting approximately 30% of live born infants. Low birth weight is a key determinant of neonatal mortality and has also been resistant to cost-effective interventions in resource poor settings. Given the lack of appropriate interventions for poor, rural areas in developing countries and the strong observational association between open burning of biomass fuel sources and ARI in young children and low birth weight, we have designed a community-based randomized trial to determine if reductions in household indoor smoke exposure can reduce the incidence and duration of acute lower respiratory infections in children <36 months of age and low birthweight among newborn infants. Household indoor smoke reduction will be accomplished by replacing the current cook stove in the household with a locally appropriate, inexpensive model that is more efficient and vented to the exterior. In addition, we will assess the impact on respiratory function and symptoms among adults in the household, including women of reproductive age, and compare total fuel consumption and time spent collecting fuel for the household. The project is a cluster-randomized, community-based trial of cookstove replacement in a rural population of southern Nepal. Households will be randomized to receive replacement of their cook stove with an appropriately designed, efficient stove that is vented to the exterior at different time periods during the course of the study. An initial period of surveillance for ARI and low birth weight will establish a baseline rate for all clusters. This will be followed by the randomized, serial replacements of cook stoves over a 12 month period. Surveillance will continue throughout this period and for an additional 6 -18 months depending on when the stove was replaced. Two cohorts of sectors will enter the trial sequentially. Measurement of indoor air particulate concentration will be conducted in a sample of households before and after stove replacement. The analysis will focus on estimating the impact on incidence of ARI in children and low birth weight among live births as a result of stove replacement. We will also assess the relative efficiency of the new stoves by identifying fuel consumption in the household and time spent collecting fuel. Approximately 4200 children 1-35 months of age will be required to observe a minimum 10% reduction in risk of ARI with 90% power. Given the expected number of live births to occur in these clusters, we can detect a 50 gram difference in birthweight with over 90% power and a type I error of 5%. PUBLIC HEALTH RELEVANCE: Lower respiratory infections and low birthweight are leading causes of death among young children in developing countries. There are few preventative measures for these problems that are cost-effective in the context of severe resource constraints. We propose to test an inexpensive approach to reducing the risk of these infections and low birthweight by reducing the exposure to airborne fine particles and carbon monoxide caused by the open burning of biomass fuel sources in the home by replacing the cookstoves with an improved, more efficient, and vented stove. If the replacement of these stoves works to reduce respiratory infections and low birthweight, significant number of children's lives can be saved at very low cost.
DESCRIPTION (provided by applicant)
Asthma is a chronic inflammatory disease of the lungs that is influenced by a combination of host susceptibility and environmental exposures. Particulate air pollution is a pro-inflammatory agent that has been associated with adverse health consequences. While much research has focused on outdoor exposures, the indoor environment is critical as Americans spend most of their time indoors and the investigators' preliminary data have demonstrated that indoor PM concentrations greatly exceed outdoor PM concentrations in urban homes. Based on preliminary data that suggest a strong association between coarse PM exposure and respiratory symptoms among those with non-allergic asthma, the investigators hypothesize that exposure to indoor coarse PM promotes inflammation and worsening of respiratory symptoms and lung function among individuals with non-allergic asthma. Using a study design that combines a longitudinal panel study and an exposure challenge model, the investigators will aim to provide evidence of a causal relationship between indoor coarse PM exposure and exacerbation of asthma status.
In specific aim 1, they will determine the effect of indoor coarse PM exposure on asthma health by conducting an epidemiologic panel study measuring in-home PM concentrations and corresponding daily variation in lung function, asthma symptoms, and biomarkers of inflammation among inner-city minority children with non-allergic asthma. In specific aim 2, they will investigate the short-term effects of coarse PM exposure on non-allergic asthma by administering a controlled, nebulized PM challenge and measuring airway reactivity and biomarkers of inflammation.
Completion of the proposed research, along with complementary training and mentorship in an outstanding and supportive environment for clinical research, will provide in-depth exposure to clinical research design, conduct, and analysis. These experiences will allow the principal investigator to become a successful, independent investigator in academic medicine.
Asthma affects more than 20 million individuals in the U.S, including over 6 million children and young adults. The proposed research investigates the effect of an environmental exposure, air pollution, on this disease process. If indoor exposure to airborne PM triggers asthma exacerbations and stimulates an inflammatory response, the findings from this study may direct new therapeutic interventions and will represent an important advancement in the treatment of asthma with profound public policy implications.
DESCRIPTION (provided by applicant): Aberrant cell proliferation and differentiation following toxic injury to bronchial epithelium can lead to the development of various respiratory diseases including lung cancer, but the underlying molecular mechanisms involved in such processes remain enigmatic. The proposed research is based on the premise that AP-1 family of transcriptional factors act as environmental biosensors to various external toxic stimuli and regulate genes involved in cell proliferation and differentiation. Recently we have shown that Fra-1 (fos-related transcription factor-1), a member AP-1 family, up regulates the gene expression involved in airway squamous metaplasia, a preneoplastic lesion. Other studies have demonstrated a protracted expression of Fra-1 in response to silica and asbestos exposure, which causes bronchial epithelial cell transformation. Furthermore, we have observed that Fra-1 expression is induced by phorbol ester PMA and tobacco smoke in airway epithelial cells both in vitro and in vivo. Therefore, we hypothesize that protracted induction of Fra-1 expression by toxicants compromises the normal bronchial epithelial cell growth and differentiation thereby altering pulmonary defense and injury-repair processes, which culminate in cellular transformation. The proposed Specific Aims to test the above hypothesis are to: 1) Define the promoter cis-acting elements and trans-acting factors that regulate PMA and tobacco smoke-inducible Fra-1 expression by in vivo footprinting, deletion/mutation and electrophoretic mobility shift assays. 2) Elucidate the signal transduction pathways that mediate PMA- and tobacco smoke-inducible fra1 expression employing pharmacological inhibitors as well as genetic mutants of various mitogen-activated protein kinases; and 3) Examine the functional role of Fra-1 in PMA- and tobacco smoke-induced bronchial epithelial injury-repair and transformation. To achieve these objectives, we will use two independent, but complementary approaches that utilize in vitro cell culture and in vivo transgenic mouse models that over express wild type or dominant negative-mutant Fra-1, specifically in bronchial epithelial cells. These studies should provide additional insight into mechanisms of toxicant-inducible gene expression and also establish the specific role for Fra-1 in lung biology and toxicant-induced respiratory pathogenesis. Also, these results should enable us to identify lung-specific Fra-1-inducible genes that might offer unique opportunity to use them as potential diagnostic markers or drug targets for early detection and prevention of respiratory pathogenesis.
DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and is a progressive disease characterized by lung injury and inflammation. Unfortunately, smoking cessation has been the only therapeutic intervention proven to slow disease progress and decrease mortality; however some people continue to have rapid loss of lung function and airway inflammation despite abstinence from smoking. These observations suggest that there may be continued exposures in the environment which act to perpetuate the inflammatory state. Endotoxin is a pro-inflammatory agent, present in cigarette smoke and ubiquitous in the environment. Chronic exposure to endotoxin in animal studies has caused physiologic changes consistent with pulmonary emphysema and human inhalational studies have shown that endotoxin causes inflammatory changes similar to those seen in the airways of individuals with COPD. Exposure to endotoxin has known adverse pulmonary consequences in workers in certain occupational settings, including obstructive abnormalities in lung function and accelerated lung function decline. Though domestic endotoxin levels are lower than those seen in occupational settings, the biological relevance of chronic exposure to these lower levels has been demonstrated by our studies as well as other epidemiological studies which link domestic endotoxin exposure with adverse health outcomes in other chronic lung diseases, including asthma. Therefore, it is a compelling hypothesis that exposure to domestic endotoxin promotes inflammation and worsening of respiratory symptoms and lung function in COPD patients; however no epidemiological studies have evaluated the effect of domestic endotoxin exposure on COPD morbidity. The proposed study will examine the effect of domestic endotoxin exposure on health status and pulmonary and systemic inflammation in former smokers with COPD. Specifically, we propose a longitudinal study to measure settled dust and airborne endotoxin levels, at baseline, 3 months and 6 months, in homes of 75 former smokers with COPD. We will measure both settled dust and airborne endotoxin concentrations in order to determine which exposure is associated with a greater risk of respiratory disease. Additionally, we propose to collect extensive phenotypic data, including respiratory symptoms, quality of life, lung function and pulmonary and systemic markers of inflammation (exhaled nitric oxide, induced sputum and serum markers). We hypothesis that higher levels of indoor endotoxin concentrations lead to lower lung function, worse quality of life, greater symptoms and increased airway and systemic inflammation in former smokers with COPD. Additionally, repeated measures of endotoxin will allow us to assess potential sources and temporal variability of indoor endotoxin concentrations. Completion of the proposed work will 1) expand the relatively small body of evidence on the perpetuation of airway inflammation and disease in COPD patients who stop smoking, 2) contribute greatly to the understanding of novel risk factors fueling the epidemic of COPD. PUBLIC HEALTH RELEVANCE: With chronic obstructive pulmonary disease (COPD) being the fourth leading cause of death in the US, with limited treatment options, understanding environmental factors which perpetuate the disease is an important public health priority. The work proposed herein will further our understanding of the effect of the domestic environment, specifically domestic endotoxin exposure, on the perpetuation of airway inflammation and progression of COPD, providing essential information in an area in which limited epidemiological investigations have been conducted to date. Our results will provide the necessary clinical and scientific foundation to develop future gene-environment interaction and intervention studies aimed at reducing endotoxin exposure in order to decrease COPD morbidity and mortality.
DESCRIPTION (provided by applicant):
4.4.6 Project Summary Abstract During Phase I, MetaMedia Training teamed with the Rail Workers Hazardous Materials Training Program to produce the prototype DVD training tool entitled }Lessons Learned from Graniteville.} The specific aim of the Phase II project is to complete the design and develop a full interactive virtual experience that will reduce the risk faced by Rail Workers, First Responders, and the community when dealing with incidents involving hazardous materials transported by rail. If First Responders and Rail Workers follow a systematic approach to handling emergency incidents, public safety and workers' safety and health will be better protected and disasters may be mitigated more rapidly. This research is relevant to public health due to the increasing level of hazardous materials being transported via rail, and the current lack of adequate training materials for emergency personnel responding to such incidents. Approximately 800,000 shipments of hazardous substances travel daily throughout the United States, frequently through densely populated areas where the consequences of an acute release could result in environmental damage, severe injury, or death. In 2006 there were three recorded instances of chlorine tank car derailments in the United States. The DVD brings to life as a facilitated training exercise the catastrophic Norfolk Southern railroad derailment that occurred in Graniteville, SC in 2005. The collision released over 11,000 gallons of chlorine gas, causing nine deaths, injuring hundreds, and displacing hundreds more civilians. We have incorporated compelling and realistic interactive video simulations of hazardous materials incidents, instructive three dimensional computer animations, and engaging team exercises to produce an effective training tool that successfully transfers knowledge as noted in the subsequent evaluation. MetaMedia's application of DVD technology will take advantage of the unique features of DVD, such as high-quality motion video, interactive branching, and low-cost delivery systems to bring real-world simulations into the classroom. The deliverables for Phase II will be a completed DVD program providing up to 4 hours of content, including recommendations resulting from the evaluation, additional components of the interactive experience, and instructor and student guides. 4.4.7 Project Narrative This research is relevant to public health due to the increasing level of hazardous materials being transported via rail, and the current lack of adequate training materials for emergency personnel responding to such incidents. Approximately 800,000 shipments of hazardous substances travel daily throughout the United States, frequently through densely populated areas where the consequences of an acute release could result in environmental damage, severe injury, or death. Exposure to chlorine gas shipments alone, traveling to drinking water and waste water treatment plants, exposes more than 25 million Americans who live near these facilities and one million more living in cities and towns along the rail delivery routes.1 DHS and security experts continue to warn of the risk for industrial chemicals used by terrorists as weapons of mass destruction. Terrorists have attacked and blown up several trucks carrying chlorine in Iraq. There are over 63,999 chemicals used outside the laboratory environment as reported by the Chemical Abstracts Service). DOT regulates over 3,800 hazardous materials in transportation, as listed in 49 CFR. EPA lists 15 chemicals that account for two-thirds of all chemical releases. Over 70% of all hazardous materials in the United States are shipped in railroad tank cars. 1 Toxic Trains and the Terrorist Threat, Paul Orun, National Labor College, Rail Workers Hazardous Materials Training, April 2007.
DESCRIPTION (provided by applicant):
MetaMedia Training International, Inc. and HazMatIQ LLC have formed a company to develop a library of Hazardous Materials courseware and related resources, integrated into a Learning Management System (LMS). The first product in the library to be developed under this SBIR grant request, HazMatIQ Four Step System, will take advantage of advanced training technologies and blended learning. Based upon HazMatIQ's highly successful classroom training delivery system, this project aims to transfer the training to an online version to facilitate a larger audience, reduce training costs, and allow 24/7 accessibility. HazmatIQ will provide responders with comprehensive training of the characteristics of hazardous chemicals, simplifying the overly complex approach currently being provided in classrooms and textbooks. In addition to the actual content related to chemical compounds, an interactive design that simulates the fidelity of a real-world emergency response involving multiple hazardous chemicals will be designed. This virtual experience will bring actual case studies to life using interactive video, 3-D animations, and graphics. The ability to deliver quality Hazardous Materials/ WMD training online has become relevant due to the increased level of technical expertise expected from Emergency Responders and the current inability of Responders to receive this training. Online training alleviates many problems faced by public safety professionals training, allowing students to train on their schedule while on duty and with the ability to start and stop in the event of an emergency incident. Traditional training on duty requires personnel to be taken out of service, leading to service gaps. Off duty training is costly since responders are traditionally paid overtime. Training is generally reduced or eliminated once funding has been exhausted. MetaMedia will use the internet to deliver high quality, job related pertinent hazardous materials and safety training to a large audience at a low cost. Accessing training at the user's convenience leads to increased training, which will convey to a safer and more effective response to a hazardous event. An LMS will track student participation and evaluation results generating a report based on specific department needs. This report can then be used by training officers to document their members' participation.
DESCRIPTION (provided by applicant): Evidence from environmental epidemiology research often contributes to the foundation of major policy decisions, driving policy makers to pose challenging questions to researchers. These questions are often best answered by using statistical methods that characterize the risk of a targeted environmental agent while taking other environmental variables into account. The nature and characteristics of environmental data and health outcomes make the risk estimation challenging and require the development of novel statistical methods. The purpose of this research is to develop models for integrated analyses of Spatio temporal data on exposure, health outcomes and covariates, incompletely observed and available at different levels of aggregation. Such models are needed for addressing a broad class of environmental agents that vary over time and across geographical regions. The focus is on the development of new statistical methods for: 1) estimating temporal associations between health outcomes and current and past environmental exposures, when the underlying function is unknown and exposure is measured with error (Aim A.1); 2) estimating spatial associations between health outcomes and environmental exposures which take proper account of non-random sampling designs (Aim A.2); and 3) conducting integrated analyses of spatio-temporal data on health and environmental exposures taking into account sources of bias arising from spatial and temporal aggregations (Aim A.3). We apply the proposed statistical methods to data on air pollution, mortality and temperature (Aim A.4).
This research will provide a unified statistical framework for analyses of environmental epidemiological data of practical importance. The work proposed here will contribute statistical methodology to the field of environmental epidemiology, and will provide evidence on health effects of air pollution and temperature through the application of the proposed methods to various data sets available to us.
Crisp Terms/Key Words: environmental exposure, clinical research, human data, temperature, human mortality, epidemiology, mathematical model, model design /development, statistics /biometry, environmental health, disease /disorder proneness /risk, air pollution
DESCRIPTION (provided by applicant): The human genome is subject to constant attack by endogenous and environmental DNA damaging agents. If unrepaired, DNA lesions will give rise to mutations that in turn may lead to cancer formation. A complex network of DNA repair pathways operates to remove DNA lesions. In order to accurately assess the biological significance of exposure to environmental DNA damaging agents, it is necessary to understand the molecular details of the complex cellular response to DNA damage. Although prokaryotes and lower eukaryotes have proven to be useful model systems for higher organisms, there are aspects of the DNA response, including DNA repair pathways that appear to be restricted to higher eukaryotes. For example, lower eukaryotes lack homologs of the genes encoding DNA ligase III, XRCC1, poly (ADPribose) polymerase-1 (PARP-1) and DNA polymerase beta. All of these proteins have been implicated in DNA base excision repair and the repair of DNA single-strand breaks. The goal of this grant is to elucidate the roles of the LIG3 and XRCC1 gene products in maintaining genome stability in mammalian cells. In preliminary studies, PARP-1 and the hRAD50/Mre11/Nbs complex have been identified as partners of DNA ligase III-alpha in somatic cells. In addition, DNA ligase III-alpha has been shown to be phosphorylated in a cell-cycle dependent manner and dephosphorylated in response to DNA damage. On the basis of these results, 4 aims are proposed: (i) to delineate the functional and biological consequences of the interaction between DNA ligase III-alpha and PARP-1; (ii) to elucidate the functional and biological consequences of the interaction between DNA ligase III-alpha and the MRE11 complex; (iii) to characterize cell cycle-regulated and DNA damage-dependent modifications of DNA ligase III-alpha; (iv) to determine the cellular functions of the LIG3 gene products by generating lig3 mutant cell lines and animals. These studies will provide novel insights into DNA transactions that are unique to more complex organisms and will contribute to an overall picture of how DNA repair mechanisms protect against DNA damage and mutations induced by exposure to genotoxic environmental agents.
Crisp Terms/Key Words: environmental exposure, binding site, enzyme activity, phosphoester ligase, DNA damage, DNA binding protein, protein structure function, phosphorylation, pentosyltransferase, DNA repair, immunoprecipitation, western blotting, gene mutation, gene expression, genome, flow cytometry, cell cycle, laboratory mouse
DESCRIPTION (provided by applicant):
To date, factors influencing the rate of decline in kidney function in children are poorly described and understood. Recent research suggests environmental exposure to lead or cadmium, even at levels considered "non-toxic" by current federal government standards, potentially accelerates kidney injury and kidney function decline in adults. Exposure is common; the entire population of the United States (US) has some measurable amount of these substances in their body. Few studies have examined the risk of low-level heavy metal exposure on kidney function in children during vulnerable periods of growth and development, and no studies have examined this in the group likely at highest risk, children with CKD. The primary objective of this proposed study will be to elucidate the association of two potential risk factors, exposure to lead and cadmium, with CKD and its progression in children. We hypothesize that lead and cadmium will independently be associated with CKD and its progression.
Due to the paucity of research in this area, the National Institutes of Health (NIH) is currently sponsoring a prospective cohort study entitled Chronic Kidney Disease in Children ("CkiD") of 540 children in the US with CKD. To accomplish the stated objectives, we propose a cross-sectional and prospective cohort study within the existing CKiD cohort to include: (1) Determination of whole blood lead and cadmium levels and urine cadmium levels by high resolution inductively coupled plasma mass spectrometry, and (2) simultaneous glomerular filtration rate (GFR) measurements, the gold-standard for the determination of kidney function, by the plasma disappearance of iohexol, at baseline and then every two years. This data will be analyzed using linear regression to determine the associations between lead and cadmium levels, adjusting for other known risk and confounding factors, and: (1) GFR, and (2) decline in annual GFR.
Environmental sources of lead and cadmium are well established and methods to reduce and treat exposures have been established, especially given the association of lead with negative neurocognitive effects over the past few decades. If lead or cadmium are proven to be associated with the decline in kidney function in this vulnerable population, screening could be recommended, and treatment, such as heavy metal abatement or even chelation therapy, could be considered. As this is a progressive disease, and lower kidney function is clearly associated with poorer quality of life and higher morbidity and mortality, any intervention that could potentially delay the inevitable decline might improve the lives of thousands of children, and potentially millions of adults, with kidney disease.
DESCRIPTION (provided by applicant)
This proposal is in response to RFA-ES-06-09, Short Term Educational Experiences for Research (STEER) in the Environmental Health Sciences for Undergraduates and High School Students is being submitted by the Department of Environmental Health Sciences at the Johns Hopkins Bloomberg School of Public Health. The title of the project is" Connecting Students to Environmental Health Researchers." Students in this proposal include both undergraduate and high school students. The central goal of this proposed program for short term educational experiences for research is to connect undergraduate and high school students with investigators involved in environmental health research at the Johns Hopkins Bloomberg School of Public Health. This research could range from studies at the molecular level up to population- based studies. Secondary goals include: 1) increasing the awareness of these students of the opportunities for research careers in the field of environmental health; 2) increasing the number of students aware of these career opportunities by accepting students from different colleges and universities and high schools; and 3) increasing the number of students that apply to undergraduate or graduate programs relevant to environmental health. In addition to their research experience, students will attend a weekly seminar and journal club in environmental health and tour various core facilities. The culminating activity of this summer research experience will be that the students, in conjunction with their mentors, will develop an abstract and poster of their research for a Research Symposium dedicated for this program. All faculty, students and staff in the Department will be invited to attend and all attendees will be given a copy of an abstract booklet. As part of the investigators' evaluation plan, they will include an exit survey. The investigators are particularly interested in learning what the students' knowledge about environmental health was when they entered the program versus when they ended the program. They will also query about their knowledge of the scientific method, and methods before and after participating. The longer-term goal is to assess whether the students that come through this program enter into undergraduate science programs (in the case of high school students), or science graduate programs (in the case of undergraduates), particularly in an environmental health related discipline.
DESCRIPTION (provide by applicant)
This is a renewal application for the "Short-Term Research Training for Minority Students" program, based in the Department of Environmental Health Sciences at the Johns Hopkins Bloomberg School of Public Health (BSPH). The central goal of this program for qualified undergraduates is to increase the diversity of students with knowledge of and who wish to go on to do graduate study in the field of environmental health sciences. Secondary goals include: 1) increasing the awareness in these undergraduates of opportunities for training and careers in the field environmental health within a public health setting; and 2) increasing the numbers of undergraduates aware of these career opportunities by accepting students from different colleges and universities across the country. Since 2001, and including incoming 2005 students, this grant has supported 23 under-represented students. Undergraduate students are recruited from applicants to the Hopkins Disparity Summer Internship Program (DSIP). Criteria for selection and appointment to this training grant include academic performance (GPA > 3.0), completion of at least 2 years of college, interest in environmental health as related to human health, letters of recommendation, and some prior laboratory experience through course work or research. In addition to working in the research program of their faculty sponsor, students in this training program participate in a weekly seminar series sponsored by participating faculty. They also participate with other students in DSIP who are working with faculty in other departments of the BSPH and with faculty in the School of Medicine, in a welcoming reception, a separate seminar series and a culminating poster session. The students receive a letter and evaluation form from the Director, and each year they are contacted and asked to provide information on their progress through their academic careers and current status.
DESCRIPTION (provided by applicant)
The NIEHS Training Program in Environmental Health Sciences has supported 62 former pre-doctoral and 24 former postdoctoral trainees since 1996. Forty-three former pre-doctoral and 20 former postdoctoral trainees are in career positions in the private sector/industry, government or academia. Combined, current and former trainees have published over 300 peer-reviewed papers and book chapters. Consistent with the new NIEHS T32 guidelines, this Training Program has been restructured and has a new mission, goals and research foci. The mission of the Training Program is to actively prepare research scientists to become future leaders of individual and interdisciplinary research projects that seek to understand the role that environmental exposures play in the etiology and exacerbation of human disease at the individual and population level. The mission will be accomplished by providing support for pre- and postdoctoral trainees involved in research on the role of exposures to environmental agents (e.g. various chemicals, metals, particulates, fungal or bacterial-derived toxicants) as causative agents or co-factors in human disease. Trainee research will focus on one or more of the following: Mechanisms of exposures to environmental agents that alter biological processes that contribute to disease pathobiology; Development of biomarkers of disease pathobiology (e.g., biomarkers of response, effect, and susceptibility to toxic agents); Development of intervention strategies based upon mechanistic studies to prevent adverse effects that contribute to disease caused by exposure to environmental agents; and Epidemiology to identify population-based associations of environmental agents with disease. The research of the training faculty is focused on investigations on the contributions of environmental agents to the following diseases: cancer, immune system diseases, neurological diseases, pulmonary and cardiovascular diseases, and reproductive and developmental diseases. The research being conducted by the faculty together with pre-doctoral and postdoctoral trainees addresses one or more of the following: 1) mechanisms of disease pathobiology; 2) development of biomarkers of the pathobiology (e.g. biomarkers of response, effect, susceptibility); 3) development of prevention/intervention strategies; and 4) disease epidemiology.
BACKGROUND
This Training Program is in its twenty-fifth year. Over the years, this Training Program has evolved and continues to evolve in order to respond to the new NIEHS guidelines. The program is both interdisciplinary and interdepartmental. The academic departments that are involved in the current application are the Departments of Environmental Health Sciences, Biochemistry and Molecular Biology, and Epidemiology. As a part of the response to the new NIEHS guidelines, a new mission statement and new goals have been developed. Faculty members whose research focus does not encompass the new mission are no longer members so that the number of faculty members that are involved in the training faculty has been reduced to 26. Additionally, there is a shift in the number of requested support for pre-doctoral and postdoctoral positions. The move is from 20 pre-doctoral positions to 14 and from 3 postdoctoral positions to 7.
DESCRIPTION (provided by applicant):
The Department of Biostatistics at the Johns Hopkins Bloomberg School of Public Health proposes an Environmental Biostatistics pre-doctoral training program to support four (4) trainees. The program entails two+ years of course work followed by examinations and a research thesis. Training grant support will be provided for the initial 3 years; research assistantships will fund the remaining training period. The program will be located in the Department of Biostatistics and be supported by faculty in the Departments of Biostatistics, Environmental Health Sciences, Epidemiology, Health Services Research, and Molecular Microbiology and Immunology. Through course work, seminars, participation in working groups and directed doctoral research, the investigators shall educate the next generation of leaders in development and application of biostatistical science to environmental research and policy. They shall integrate biostatistics and biostatisticians with other environmental sciences in an educational climate ideally suited to fostering lasting relationships among graduate students and faculty in biostatistics and other fields. As a result, the graduates will effectively collaborate across disciplines, identify the key methodologic needs, then develop and apply statistical approaches that address these needs. Graduates will effectively communicate substantive findings to scientists, policy makers and the general public. Program and affiliated faculty are committed to honoring this philosophy and to achieving these goals.
DESCRIPTION (provide by applicant)
This application is for continuation of a toxicology training program at University of Maryland (UM). The objective is to train graduate students and postdoctoral fellows in neurotoxicology, cell injury and carcinogenesis, molecular epidemiology and aquatic toxicology, with special emphasis on mechanisms and application of cutting-edge technologies to toxicological research. This proposal brings together a cadre of well funded, highly productive faculty mentors from different sites within the UM System, including the School of Medicine (SOM) and the Chesapeake Biological Laboratory. Mentors form a cohesive program designed to prepare trainees for research careers in toxicology and environmental health sciences. One of the major strengths is the exposure of the students to translational aspects of basic research in toxicology. Chemical risk assessments and the development of countermeasures to treat and/or prevent disease states induced by toxicants depends on the determination of the mechanisms by which such toxicants act, on the identification of targets for therapeutic intervention, and on the characterization of new assays, models, tools, and technologies for toxicity testing. Thus, mentors have been selected for their common interest in basic, clinical and ecological research applied to such environmental toxicants as metals, phytoestrogens, dioxins, and insecticides, and interests span from basic to clinical and environmental research. This selection provides trainees with a unique opportunity to gain experience in fields that play a major role in determining the mechanism of action and the effects of environmental toxicants in susceptible subsets of the population, including sensitive stages of development. The graduate training in toxicology combines resources of the UM system-wide Program in Toxicology and the SOM Pharmacology and Experimental Therapeutics Departmrnt (toxicology track), and includes didactic course work, laboratory rotations, seminars, research and participation in national meetings. The postdoctoral program includes training in state-of-the-art toxicology research, teaching experience, and participation in seminars and national meetings. The breadth of the program is sufficient to allow emphasis in four primary areas: The Neurotoxicology Track provides training in molecular mechanisms of neurodegeneration due to environmental toxicants and the development of chemo- and gene therapy modalities. The Cell Injury and Carcinogenesis Track provides training in the action of free radicals, calcium homeostasis, mechanisms of lead and dioxin toxicities, estrogen biosynthesis and carcinogenesis. The Molecular EpidemiologyTrack provides training in identification of biomarkers of exposure and susceptibility, and in epidemiological methods for identifying associations between environmental chemical exposures and diseases. The Aquatic Toxicology Track provides training in pathobiology, immunotoxicology and molecular mechanisms of toxicity of heavy metals, dioxin and other pollutants.
DESCRIPTION (provided by applicant)
The Center to Protect Workers' Rights is applying for RFA-ES-04-006, Hazmat Training at DOE Nuclear Weapons Complex for a total cost of $2,461,399.
The objective is to ensure construction workers called upon to work on DOE sites have the training they need to protect their health and safety, and that of their co-workers families, their communities, and the environment. The target population, represented by the 11 international/national construction unions the applicants have assembled in this proposed training consortium, perform a vast array in hazardous waste operations, decommissioning and decontamination, transportation, restoration and emergency response activities.
CPWR is a 501(c)(3) organization created by the Building and Construction Trades Department, AFL-CIO. As such, they are uniquely positioned to carry-out the training programs proposed in this application. There is significant support from affiliated construction unions and employers, as evidenced by their past performance as an NIEHS grantee. To meet the training needs of the target population working in and around DOE sites, CPWR and its training consortium proposes to train 6,499 trainers and workers in Year 1, and 31,930 trainers and workers over the five-year period of the proposed cooperative agreement.
DESCRIPTION (provided by applicant)
Our objective is to ensure construction workers called upon to work in EPA Superfund environments and also in disaster response, have the training they need to protect their health and safety, and that of their coworkers families, their communities, and the environment. Our target population, who are represented by the 11 international/national construction unions we have assembled for this proposed consortium, perform a vast array of remediation and construction tasks at hazardous waste sites. They also provide essential skills in support of first responders in their role as skilled support personnel.
CPWR is a (c)(3) organization created by the Building and Construction Trades Department, AFLCIO. As such, we are uniquely positioned to carry-out the training programs proposed in this application. We have significant support from our affiliated construction unions and employers, as evidenced by our past performance as an NIEHS grantee. To meet the training needs of our target population engaged in hazardous waste activities, CPWR and its training consortium propose to train 5,080 trainers and workers in Year 1 under HWWT, and 1,000 trainers and workers in Year 1 under HDPT.
With our strong connections in industry as an organization created by Construction Unions, in this application we also propose to continue our MWT program, which also has had tremendous success over the years. We would like to continue programs in Baltimore, New Orleans and Oakland, and start an additional one in Denver, training a total of 95 students in Year 1. Under BMWT we propose to continue our current programs in Boston, East Palo Alto, Los Angeles, and St. Paul. Our programs have been very successful in placing program participants in meaningful jobs in environmental remediation.
DESCRIPTION (provided by applicant)
The long-term goal of the Center for Childhood Asthma in the Urban Environment (CCAUE) is to understand how exposures to indoor and outdoor airborne particulate matter and allergens may result in airway inflammation and respiratory morbidity in children with asthma living in the inner city of Baltimore and to identify novel opportunities and strategies to reduce morbidity associated with these exposures. The overarching hypothesis guiding the Center's proposed research is that indoor air pollution (particulate matter and allergens) produces increased oxidative stress which leads to increased airway inflammation and asthma morbidity in children. The investigators have assembled a multidisciplinary and integrated team of researchers to investigate the role oxidative stress, and airway inflammation in asthma morbidity in order to develop new biomarkers of effect, provide insight into susceptible genotypes, offer better clinical management, and to identify opportunities for intervention (environmental and pharmacologic).
This program outlines a multidisciplinary program directed to address this hypothesis and long-term goal. This Center application includes the following two clinically-oriented and mechanistically-oriented research projects: Clinically-Oriented Research Projects: Project 1 - Domestic Indoor PM and Childhood Asthma Morbidity; Project 2 - Oxidative Stress/Inflammation during PM Nasal Challenge and Mechanistically-Oriented Research Projects: Project 3 - Nrf2 Dependent Regulation of Oxidative Stress in Asthma; Project 4 - Mechanisms of PM-Induced Dendritic Cell Activation.
INTEGRATED (clinical and basic) and INTERDISCIPLINARY NATURE OF PROGRAM
DESCRIPTION (provided by applicant)
This proposal requests partial funding (~25%) for 2008 Summer FASEB (Federation of American Societies for Experimental Biology) conference on "Biological Methylation: from DNA to Histones". The meeting will focus on the forefront research of epigenetic methylation and its influences on human illnesses, which is one of the current major missions of the NIEHS. The conference will be held in the Carefree Resort, Carefree, Arizona, from June 1-6, 2008 (Sunday-Friday). The FASEB Biological Methylation Conference is one of the most stimulating and important meetings in the field, where approximately 150 scientists (including many established women scientists, younger scientists, graduate students, and postdoctoral fellows) assemble to coordinate, exchange, and disseminate information and to explore epigenetic factors (such as environmental factors, individual susceptibility and age) on human illnesses. One keynote speaker, 9 session chairs, 36 invited speakers and 18 speakers (young scientists) selected from submitted abstracts will address the following 9 major themes: 1) eukaryotic cytosine methyltransferases; 2) link DNA methylation to histone methylation; 3) histone lysine methylation and recognition; 4) protein arginine methylation; 5) DNA methylation and diseases; 6) epigenetics and cancers; 7) histone demethylation; 8) methylation other than histones or nucleic acids; and, 9) small molecule enzyme inhibitors. In addition, three afternoon mini-symposia are devoted to young investigators.
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