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Record Count: 42
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DESCRIPTION (provided by applicant): Exposure to ferrous-like metals lead to multiple toxic endpoints, including lung and erythropoietic abnormalities, and cancer. Many different mechanisms have been proposed to explain the toxicity of ferrous-like metals. Our preliminary data and recent publications suggest that the hypoxia signaling system may play a role in metal induced injury. The ability to sense and cope with low oxygen tension, or hypoxia, is critical to normal physiology and several pathological conditions. Organisms have developed a mechanism of coping with hypoxia and central to this process are the hypoxia inducible factors (HIFs). HIFs are inducible transcription factors that regulate the expression of a battery of genes essential to dealing with a hypoxic environment. These hypoxia responsive genes are also affected by ferrous-like metals, such as cobalt and nickel. Recently, a family of prolyl hydroxylases was identified that act as oxygen sensors for the HIF proteins. These enzymes can be inhibited by ferrous-like metals and offer a link between hypoxia and metal exposure. This intersection has led us to the following hypothesis: HIF mediated transcription is necessary for cellular damage and lung toxicity caused by exposure to ferrous-like metals. To address this hypothesis five specific aims are proposed: 1) Create and characterize ARNT deficient cells. 2) Characterize the role of HIF signaling in metal induced toxicity with HIF deficient cell lines. 3) Determine whether metal induced toxicity is dependent upon stabilization of the HIFs through inhibition of prolyl. hydroxylation. 4) Determine the role of HIF regulated genes in mediating metal induced toxicity using RNAi. 5) Determine whether HIF mediated signaling is necessary for metal induced lung toxicity using HIF1 n and ARNT conditional null mice. The completion of the proposed research will increase our understanding of the signaling mechanism used by ferrous-like metals. The studies will link ferrous-like metals to the hypoxia response pathway and its down-stream target genes. The proposal will create a set of cell lines that will have broad interest in several fields, including oncology, toxicology, and pharmacology. In addition, the understanding we gain about hypoxia and HIF mediated signaling will have benefits to developmental and cancer biology. Finally, these studies will elucidate the role of hypoxia signaling in metal induced toxicity in vitro and in vivo.
DESCRIPTION (provided by applicant): As a major detoxicating enzyme in human liver, hydroxysteroid sulfotransferase (SULT2A) catalyzes the sulfonation of biologically important endogenous and xenobiotic substrates, including hormones, cholesterol intermediates, pharmaceuticals and procarcinogens. Sulfonated sterol metabolites are emerging as novel candidates for the modulation of nuclear receptor activity in the liver. We previously demonstrated that SULT2A transcription is regulated by lipid-sensing nuclear receptors in human and rodent liver. Recently, hyposulfatemic mice with nullified expression of a renal sulfate transporter were found to develop altered hepatic lipid and cholesterol metabolism along with selectively induced expression of hepatic SULT2A. These results suggest a role for sulfate homeostasis as an under-studied facet of metabolic disease. Our hypothesis is that hepatic SULT2A1 is an environmentally-sensitive determinant of liver X receptor (LXR) signaling. SULT2A1 catalyzes the sulfonation of endogenous sterols, thereby modulating the expression of LXR target genes, including SULT2A1 itself. SULT2A1 transcription is regulated (1) by the xenobiotic-sensing receptor, pregnane X receptor (PXR), through interactions involving hepatocyte nuclear factor 41 (HNF41) and (2) under conditions of sulfate depletion, through the above-described LXR-mediated autoregulatory mechanism. The specific aims of the proposed research are to: (1) Define the roles of HNF41 and PXR in the modulation of human hepatic SULT2A1 transcription by rifampicin, (2) Define the mechanism mediating SULT2A up-regulation in response to hyposulfatemia, (3) Identify endogenous hepatic sterols that represent physiological substrates for SULT2A1, and (4) Determine the abilities of sulfonated sterols, relative to their unsulfonated counterparts, to function as modulators of human LXR activity. Overall, this work has implications for metabolic disturbances in cholesterol and sulfate metabolism in humans, and will provide new insights into the interactive roles of nuclear receptors and endogenous intermediates as modulators of xenobiotic detoxication and metabolism in human liver. PUBLIC HEALTH RELEVANCE: Project Narrative Atherosclerosis has been aptly called a "liver disease of the heart" (Davis and Hui, 2004). The environmental modifiers of hepatic lipid metabolism that favor the genesis of insulin resistant diabetes and coronary artery disease are presently unknown. However, a prime candidate is "cholesterol sulfotransferase" (SULT2A1), a drug- and hormone-metabolizing enzyme in human liver that we hypothesize plays a major role in the control of the essential lipid metabolism pathways leading to heart disease. The proposed research will shed new light on the environmentally-sensitive components of cholesterol metabolism in human liver that serve as a prelude to diabetes, liver and heart disease in humans.
DESCRIPTION (provided by applicant):
Hypomethylated T cells aberrantly overexpressing the methylation sensitive genes CD11a, IFN-gamma, perform and CD70 have been implicated in the pathogenesis of human lupus. Recent studies from this group demonstrate that KIR genes, implicated in acute coronary syndromes (unstable angina and myocardial infarctions), are also methylation sensitive and overexpressed on lupus T cells. Preliminary studies suggest that methylation sensitive T cell gene expression can be increased by restricting either folate or Met, or by decreasing DNA methyl transferase (DNMT) enzyme activity with direct/specific inhibitors, signaling inhibitors, or SAH, and that these effects are additive. Further, supplementation with either Met or folate decreases or prevents overexpression of the methylation sensitive genes by these inhibitors. These results suggest that decreases in DNMT expression due to environmental xenobiotics affecting transferase levels or function, together with dietary influences, are additive in affecting methylation sensitive gene expression, and ultimately causal in the development of lupus and its complications. These results also suggest that dietary supplementation of one or more nutrients involved in DNA methylation may be protective. These hypotheses will be tested by comparing the effects of: 1) nutrient restriction/supplementation and DNA methylation inhibitors alone and in combination on the expression and methylation of T cell CD11a, CD70, IFN-gamma, perforin and KIR and determining the consequences on cytotoxicity for macrophages and endothelial cells, 2) nutrient restriction and supplementation in vitro on the expression and methylation of methylation sensitive genes in T cells from subjects with lupus and normal controls, and 3) control, methyl-donor deficient, and methyl-rich diet on the expression of methylation sensitive T cell genes and lupus severity in mice with autoimmunity caused by an inducible ERK pathway signaling defect. Evidence that dietary modification can ameliorate aberrant gene expression in vitro and disease severity in the murine model will lead to studies extending these results to lupus patients.
DESCRIPTION (provided by applicant): Considerable toxicological research on polycyclic aromatic hydrocarbons (PAHs), which are prevalent compounds in cigarette smoke that contribute to cancer, has focused on their genotoxic attributes. However, cancer is not solely the consequence of non-reversible mutagenic events but also include reversible, epigenetic events. Thus, there is a need to reassess the toxicity of PAHs at the epigenetic level. Gap junctional intercellular communication (GJIC) centrally modulates signal transduction pathways that epigenetically alters gene expression. There is considerable evidence linking abnormal regulation of GJIC with the nongenotoxic steps of tumor promotion. Mitogen activated protein kinases (MAPKs) also play a central role in cell signaling. We will use a series of environmental and tobacco smoke-relevant PAHs and determine structure-activity relationships with inter-and intracellular signaling mechanisms in pluripotent mammalian epithelial cell lines. We will specifically test the hypothesis SA#1 that phospholipases are the upstream regulators of GJIC and MAPK in response to PAHs by using specific phospholipase inhibitors and the emerging and powerful technique of silencing genes using small interfering RNA. We will use chromatography and state of the art proteomic techniques to test the hypothesis SA#2 that lipid-derived second messengers are released from the plasma membrane, and activate cell signal proteins. We will also test the hypothesis SA#3 that inhibition of GJIC and activation of MAPK by PAHs will induce mitogenesis, and block apoptosis and differentiation. We would like to note that the use of biologically active versus inactive PAH isomers for all of the aims allows us to systematically identify molecular events that are specific to the regulation of GJIC and MAPK and subtract out non-specific events. Overall, determining the effect of environmental and tobacco-relevant PAHs on key signaling events would provide invaluable mechanistically based information on the epigenetic toxicity of these compounds, thereby aiding in the development of preventative and therapeutic strategies for cancer.
DESCRIPTION (provided by applicant): Asthma is the most common chronic disease of childhood in the United States. Children living in poverty and in urban centers, many of whom are persons of color and are at greater risk for environmental exposures, suffer disproportionately from asthma. Many important triggers of asthma, including allergens and airborne particulate matter (PM), occur in the indoor environment. Given the complex interaction of physical and social environmental factors on childhood asthma, there have been increasing calls for comprehensive strategies using a community-based participatory research (CBPR) approach. Community Action Against Asthma is a long standing CBPR partnership in Detroit, Michigan, composed of representatives from community-based organizations, health and human service agencies and academia. This CBPR intervention is a randomized controlled trial of the efficacy of air filters (AFs) and air conditioners (ACs) to reduce indoor PM and improve health status of children with asthma above and beyond a standard community health worker home visit intervention (standard). The specific aims are to:1) test the efficacy of AFs separately and when combined with ACs to reduce exposure to indoor PM, over and above a standard intervention; 2) test the association between the use of AFs separately and with ACs and the health status of children over and above a standard intervention; 3) elucidate the causal pathways by which any intervention- related improvements in children's asthma-related health status occurs; 4) communicate and disseminate research findings to multiple audiences; 5) enhance our partnership and gain an increased understanding of factors that facilitate and impede the use of a CBPR approach to environmental health research through a process and impact evaluation. 200 households in Detroit, Ml with at least one child with persistent asthma (mild to severe) will be enrolled and will be randomly assigned to a control group (receiving the standard intervention) or the intervention group (receiving the standard intervention plus AFs initially and ACs added later). Extensive exposure and health measures will be undertaken throughout the 20 month intervention. Given the role of the indoor environment triggers in childhood asthma, there is a need to test the efficacy and efficiency of novel approaches to reducing indoor air pollutants. A CBPR approach will enhance the relevance of this research, and increase the likelihood of successfully improving the health of urban children.
DESCRIPTION (provided by applicant): The burden of childhood asthma disproportionately affects children living in poverty and in urban centers, many of whom are minority ethnic groups. For those living in urban environments with high traffic densities, there is increasing concern about potential adverse respiratory health effects of exposure to diesel and other vehicular exhaust. Epidemiologic studies have shown associations between exposure to high traffic volumes, and especially to high truck traffic - the main source of diesel exhaust in urban settings - and increases in asthma symptoms, asthma hospitalizations, and decreased lung function. Yet, owing to the challenges of separating diesel from spark ignition exhaust, and vehicular exhaust in general from other sources of pollution, quantitative associations between exposure to diesel and other vehicular exhaust and adverse respiratory health outcomes have not been well-characterized. This study will characterize ambient exposures related to vehicular exhaust and other specific air pollutant sources, and evaluate the relationship of these exposures to the exacerbation of asthma among children living in Detroit and Dearborn, Michigan. We will collect ambient and indoor household air quality data which provides both high temporal and spatial resolution of pollution concentrations and utilize state-of-the-art statistical/geospatial models to apportion exposures among pollutant sources including diesel and other vehicular exhaust and to develop individual- specific exposure estimates. We will conduct a two-year longitudinal study involving 210 asthmatic children with 70 each living near high traffic/high truck volume roads, near high traffic/low truck volume roads, and distant from high traffic roads. Daily health measures to be assessed for two consecutive weeks in each of eight seasons will include respiratory symptoms, pulmonary function assessed by hand-held spirometers, medication use, and health services utilization. We hypothesize that: 1) exposures specific to diesel and other vehicular exhaust will be stronger predictors of adverse health status among children with asthma living in a high traffic density urban environment than other pollutant sources, and, 2) the presence of cigarette smokers in the household, high levels of common allergens in household dust, or sensitization to such allergens, will yield stronger exposure-response relationships between diesel and other vehicular exhaust and adverse respiratory health outcomes.
DESCRIPTION (provided by applicant): Heavy metal poisoning by elements such as mercury, lead, cadmium, and arsenic is a significant human health problem. Understanding the interaction of heavy metals with proteins is essential for defining the mechanism of toxicity, developing ways to minimize human exposure and to provide therapeutic regimens for removal of toxic ions.
Our goals are (1) to develop peptide systems that provide a groundwork for the understanding of metalloregulatory proteins and metallochaperones, (2) to develop peptidic systems that can efficiently and selectively sequester heavy metal ions from aqueous solutions, and (3) to understand the thermodynamics and kinetics of metal binding to these designed peptides.
To achieve these goals we will use a de novo peptide system based on the three-stranded coiled coil peptide aggregate motif that encapsulates with high affinity single heavy metal ions and provides spectroscopic models of mercury, cadmium and arsenic binding sites in biological systems. We will generate high resolution structures of this peptide system in the presence and absence of these heavy metals, elucidate the kinetic and thermodynamic mechanisms of heavy metal encapsulation, and expand the array of characterized systems to transition metal ions Fe(II), Cu(I), Ni(II), Co(II) and Zn(II). We will also extend the original design to include single chain peptides that encapsulate heavy metals and coiled coils that provide different coordination environments than the original design and those that encapsulate more than one heavy metal ion.
These studies will expand the foundation of knowledge that has been laid by the scientific community investigating metallopeptide design, metalloregulatory proteins and heavy metal detoxification. These objectives will develop insight into the interplay between metal coordination and apopeptide structure in defining the overall metallopeptide fold, an important aspect of metallopeptide design. Also, development of highly efficient and specific heavy metal sequestering peptides could, ultimately, provide a viable and biodegradable means of removing heavy metals from contaminated water.
Crisp Terms/Key Words: molecular chaperone, detoxification, toxin metabolism, protein structure, water solution, crystallization, synthetic peptide, mercury poisoning, lead poisoning, metal poisoning, arsenic, cadmium, heavy metal, metalloprotein, metal complex, thermodynamics, nuclear magnetic resonance spectroscopy, peptide chemical synthesis, chemical kinetics, chemical binding
The overall objective of the two proposed Center Collaborative Research Projects is to fill specific gaps in our knowledge of the impact of in utero, early postnatal and pubertal environmental exposures on mammary gland development at the cellular, molecular, organ and population levels and their influence on future breast cancer risk. This will be accomplished through 1) an epidemiological study to identify early exposures that can influence breast cancer
risk through their effects on breast development in utero through puberty. This study takes advantage of a unique opportunity to follow-up a multiethnic cohort of 500 girls ages 4-11 for whom we have extensive in utero exposures and birth characteristics information and the opportunity to prospectively collect their childhood exposures that influence their hormonal milieu (estrogens, antiestrogens) and growth (diet, exercise, stress, insulin biomarkers), identify relevant genetic polymorphisms and relate them to the timing of pubertal development. 2) The second collaborative research project will use the mouse mammary gland model to determine the molecular mechanisms of mammary gland pubertal development and maturation through in vivo and in vitro studies on the mechanism of progesterone action focusing on the roles of PRA and PRB isoforms. In parallel with the epidemiological studies, the effects of in utero, lactational and
postnatal exposures to environmental estrogens, antiestrogens and diet on mammary gland pubertal development and maturation will be determined. Finally, the effect of these environmental exposures on subsequent susceptibility to mammary tumor development will be determined. The overarching hypothesis is that in utero, lactational/formula feeding and post-lactational/childhood exposures to environmental stressors that affect the timing of pubertal
development and sexual maturation impact on breast cancer risk. We specifically hypothesize that accelerated pubertal development and early onset of menarche increase breast cancer risk by increasing lifetime exposure to progesterone acting in concert with estrogen.
To facilitate the inclusion of community concerns into Center Research Projects we will partner with community advocates and other stakeholders, and be responsive to the input from community-based, faith-based and advocacy organizations that are interested in breast cancer and environmental risks.
To optimize translation of new findings into the most effective risk minimization, the Community Outreach and Translation Core will develop strategies and tools to transmit the information to populations of women and girls, as well as community stakeholders and policy-makers.
The Wayne State University (WSU) Center for African American Urban Health is a 5-year proposal that consists of five Cores and four Projects with participation of 34 investigators from various Departments, Centers, and Programs across the WSU campus. The Center has invested heavily in coalescing and expanding a shared research infrastructure that is widely accessible to investigators. The four Cores represent specialized areas of expertise and services required to undertake testing of multi-level hypotheses related to research in racial health disparities. These Cores form the foundation of our application. The Cores are: 1) Psychosocial and Community Measures; 2) Recruitment and Clinical Assessment; 3) Biostatistics and Research Database; and 4) Genomics Core. These Cores allow the investigators to test a broader range of Project-specific study hypotheses in a more cost-efficient manner than would be possible with stand-alone Projects. African Americans were selected as the exclusive study population for the Center because of their high burden of obesity-related disease such as breast cancer and cardiovascular diseases (hypertension, heart failure, diabetes mellitus, and coronary heart disease). Also, while Detroit has the third largest population of African Americans, it has the highest percentage (81.6%) of African Americans of any major city in the USA. The four Projects are: 1) Project 1: Obesity, Nitric Oxide, Oxidative Stress and Salt Sensitivity, 2) Project 2: Weight Loss in Breast Cancer Survivors, 3) Project 3: A Dyadic Intervention for Cardiac Rehabilitation Patients, and 4) Project 4: Promotion of Healthy Behavior in African American Women. These Projects are thematically linked through obesity, diet and other lifestyle factors including physical activity, and obesity-related cardiovascular disease and cancer. Our research efforts are focused on understanding the mechanisms operating at multiple levels (environment, lifestyle, physiology, genetics) mediating known disparate chronic conditions and their precursors. We also seek to identify preventive strategies and therapeutic approaches that might alleviate the disproportionate burden of disease. Primary as well as interactive effects of environmental exposures (household and community-level) and psychobehavioral characteristics with physiological measures (e.g., 24-hour BP burden and oxidative stress), genes, and body composition will be explored in relation to their impact on study outcomes.
Crisp Terms/Key Words: health disparity, cardiovascular disorder risk, clinical research, African American, human subject, disease /disorder prevention /control, obesity
A competitive renewal is submitted for the EHS Center in "Molecular and Cellular Toxicology with Human Applications" headquartered in the Institute of Environmental Health Sciences (IEHS) at Wayne State University (WSU). The focus of the Center is the stimulation of collaborative interdisciplinary, multidisciplinary research employing contemporary molecular, cellular, genomic and proteomic approaches to the study of environmental agent (e.g. organochlorines/PAH/solvents and particulates; major urban/Southeastern Michigan concerns) effects on gene expression, cell signaling and function, and human populations. Disease emphasis includes asthma, hepatic dysfunction in metabolic diseases (e.g. diabetes, inflammation, dislipidemias), reproductive and neurological disorders, and cancer. Progress includes 12 multi-investigator grants ($43 M), numerous collaborative grants, 93 collaborative
and 411 total publications, research integrating population and bench scientists, and institutional investment. The EHS Center consists of an Administrative Core, three Research Cores, four Facility Cores, a COEP, a Pilot Project Program and an Enrichment Program. The Research Cores, "Gene Regulation and Genetics", "Cell Signaling and Function" and "Environmental Epidemiology", contain 43 faculty from three schools/colleges, three centers and five departments. The
"Cell Culture", "Imaging and Cytometry", "Microarray and Bioinformatics" and "Protein Interaction and Proteomics" Facility Cores exist in dedicated space with assigned personnel to support research. The Microarray and Bioinformatics Facility Core includes Agilent and ABI equipment, Sun computers, analysis software (e.g. Rosetta Resolver(R) and bioinformatics expertise to assist with global gene expression analysis and the association of genetic factors (i.e. SNPs
(polymorphisms), mutations) with disease. A Protein Interaction and Proteomics Facility Core has been initiated with the purchase of major equipment. An active COEP, with emphasis on K-12 education, has been developed and includes K-12 curricula, science camps, competitive science awards, high school teacher training, and dissemination of information to the community. The Pilot Project Program contains escalating incentive funding for collaborative, interdisciplinary, multidisciplinary research proposals; supplemental funds for scored, not funded, grants may be
provided. Professional growth is stimulated through an Enrichment Program (i.e. a seminar series and an Annual Thematic Symposium offering Category I Continuing Medical Education credits). Institutional commitment is shown by the hierarchal position of the IEHS in WSU, by assigned tenure track positions, by approximately $1,000,000 in equipment purchases, and by past (approximately $240,000) and future cost sharing of the Pilot Project Program (approximately $300,000). The EHS Center, reviewed annually by the External Advisory Board, provides Center Members with the opportunity and resources for collaborative interdisciplinary/multidisciplinary research, involving bench scientists, bioinformaticists, structural biologists, population scientists, physician-scientists and graduate students, to examine the role of environmental agents in disease.
Crisp Terms/Key Words: clinical research, human subject, environmental toxicology
DESCRIPTION (provided by applicant)
Support is requested to continue human health-oriented research on risks from exposure to chemicals commonly found in Superfund sites and on remediation technologies to eliminate the potential for exposure to chemicals from those sites. The pollutants under investigation are a subclass of chemicals belonging to the halogenated aromatic hydrocarbon family that bind and activate the aryl hydrocarbon receptor (AhR).These chemicals, which include chlorinated dibenzo-p-dioxins, dibenzofurans, biphenyls and polycyclic aromatic hydrocarbons, are environmentally persistent lipid soluble compounds that accumulate in the food chain and lead to human and wildlife exposure. A highly integrated, multidisciplinary research program is proposed consisting of seven research projects and four supporting core units. The research team of 27 investigators includes faculty at Michigan State University (20), CUT Centers for Health Research (4), Rutgers (2), and Purdue University (1). The central overarching theme of the proposed new program is to define specific aspects of environmental, microbial and mammalian biomolecular responses to environmental contaminants that act as ligands for the AhR. The major research thrusts are in three areas: (1) characterizing the diversity of dehalogenases and oxygenase gene sequences in microbial populations indigenous to soils, sediments and groundwater that metabolize AhR ligands; (2) defining the geochemical parameters governing adsorbtion, bioavailability and long-term fate of AhR ligands through interactions with clays; and(3) elucidation and computational modeling of the biochemical pathways and their interactions with the ligand-activated AhR, which cause altered responses in the liver and the immune system, specifically in Bcells. Two major goals of the new program are to characterize molecular mechanisms of AhR ligand interactions with specific abiotic and biotic processes and to develop new tools that can be used to more accurately estimate the fate, microbial biotransformation and human risk associated with AhR ligands contaminating the environment. Two support core facilities will assist the biomedical projects, one in the areas of bioinformatics and a second in developing dynamic computational models of mammalian biological responses induced by AhR ligands. A third core facility will provide support for the non-biomedical projects in three areas related to analysis of microbial-derived enzymes: microarray development and enhancement, automated bioinformatics analysis of PCR product sequences and biodegradative gene clusters, and high throughput screening and sequencing. In addition, a Research Translation core will communicate important research findings and outcomes emanating from the program to appropriate target audiences in government, industry and academia.
DESCRIPTION (provided by applicant):
Preterm birth is the leading cause of perinatal mortality and is associated with long-term adverse health consequences for surviving infants. No effective means for prevention of prematurity currently exists, and with preterm birth rates rising in the United States and worldwide, investigating possible causal mechanisms is a global public health priority. A recent Institute of Medicine Report notes that air pollution exposure may be a significant cause of prematurity, but most published studies are based on population birth registries and lack the individual, clinical data needed to elucidate possible biological mechanisms mediating these epidemiological associations. This proposed work presents a unique opportunity to study those mechanisms in a new cohort of 800 pregnant women residing in diverse regions of Mexico City, a mega-city with high air pollution levels. The investigators will advance the understanding of prematurity by investigating how air pollution and inflammation may act together to influence the outcome of pregnancy, and whether certain periods of gestation represent critical time windows and opportunities for preventive interventions, both clinical and environmental. The investigators will obtain biomarkers relevant to inflammation and preterm delivery (IL-1¿, IL-1ra, IL-6, IL-8, IL-10, TNF-a) in cervico-vaginal exudates provided by participants monthly during their pregnancies, along with information on infections, health history, clinical characteristics, diet and time-activity patterns. State-of-the-art exposure assessment techniques will be used to evaluate spatial and temporal variability in air pollution exposure using data from the Mexico City Metropolitan Area (MCMA) air quality monitoring network (PM2.5, PM10, ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide), matched to locations of participants' homes. At birth, DNA samples from mother and infant will be used to type three genetic cytokine polymorphisms (TNF-a, IL-1¿, IL- 1ra) that have been associated with enhanced risk of preterm birth. The investigators will evaluate whether ambient pollution is associated with preterm birth, controlling for other risk factors; whether they are associated with cytokines during pregnancy, and which time windows are most relevant. The investigators will examine effect modification by intake of antioxidant vitamins (E and C) and cytokine polymorphisms. Finally, the investigators will complement this epidemiological study with a parallel toxicology in vitro study which will involve collecting and characterizing air pollution particle samples (PM10 and PM2.5) on a monthly basis from five zones in MCMA and exposing a monocytic cell line (J774A.1) to evaluate expression of the same cytokines. Any coherence between the human and in vitro evidence for a mechanistic association between pollution and these mediating molecules will guide future studies. This multi-disciplinary, global health collaboration will evaluate potential environmental and clinical determinants of preterm delivery, with the goal of developing unique knowledge with far-reaching prevention implications.
DESCRIPTION (provided by applicant): Prenatal exposures to PCBs and methylmercury have been linked prospectively to developmental deficits in children. The data from at least one important study are controversial, however, because the children were exposed simultaneously to high levels of both contaminants. The Inuit in Canada and Greenland are among the most heavily exposed populations to these substances, due to their bioaccumulation in fish and sea mammals, staples of the Inuit diet. On the other hand, the traditional Inuit diet is also rich in omega-3 fatty acids, which are known to promote early CNS development, and in selenium, which may protect against mercury effects. We have recently conducted a study of 215 infants in Northern Quebec and are currently completing data collection on an additional 78 infants in Greenland. Although the children have been exposed to significant levels of both contaminants, the exposures are only moderately confounded in these cohorts, and preliminary data analyses suggest that each contaminant affects distinct domains of cognitive function.
The proposed study will follow up these two cohorts of Inuit children at 7.5 years of age. The aims are (1) To determine more specifically which developmental endpoints are related to which contaminants; (2) To examine neural processes that may mediate the effects on these endpoints by assessing event-related potentials and eyeblink conditioning; (3) To test the hypothesis that the deficits associated with PCBs are mediated by reductions in thyroid hormone availability; and (4) To determine the degree to which omega-3 fatty acid and selenium intake can protect against these adverse effects. This study benefits from the close ties that our Canadian and Danish collaborators have forged in these Inuit communities and provides a unique opportunity to address these issues in children whose exposures are among the heaviest on earth.
DESCRIPTION (provided by applicant): The trichothecenes, a large group of fungal toxins that are commonly encountered as food contaminants, have been etiologically linked to human gastroenteritis worldwide and are of further concern for their potential use in chemical terrorism and warfare. Trichothecenes and other ribosome-directed agents (eg. ricin, shiga toxin) activate mitogen-activated protein kinases (MAPKs) and subsequently initiate inflammatory gene expression and apoptosis via a mechanism known as the "ribotoxic stress response", however, little is known of the specific signal transduction mechanisms involved. The objective of this proposal is to identify the intracellular signaling pathways and mechanisms by which the model trichothecene deoxynivalenol (DON or "vomitoxin") induces p38 MAPK activation and relate these to inflammation and apoptosis. Our central hypothesis is that double stranded RNA-activated protein kinase (PKR) and hematopoietic cell kinase (Hck) are critical for trichothecene-induced p38 activation and downstream toxicity. To test this hypothesis, our research team will use 1) knockout mice to verify roles for PKR and Hck in p38 activation and downstream toxicity and 2) macrophages to elucidate signal transduction elements that link DON to p38 via PKR and Hck. Four specific aims are proposed: 1) Characterize the role of PKR in DONinduced p38 activation and downstream toxic effects; 2) Characterize the role of Hck in DON-induced p38 activation and downstream toxic effects; 3) Assess role of the ribosome in DON-induced p38 activation; and 4) Evaluate role of Toll-like receptors in DON-induced p38 activation. This project will enhance public health by: 1)improving molecular understanding of how these trichothecenes and ribotoxic chemicals disrupt gut immunity, 2) enhancing our capacity to assess and manage risks associated with exposure to these agents and 3) generating mechanism-based strategies for preventing and/or treating toxicity in persons exposed to these compounds via natural contamination or chemical terrorism/warfare.
Crisp Terms/Key Words: laboratory mouse, small interfering RNA, toll like receptor, JUN kinase, protein protein interaction, mitogen activated protein kinase, enzyme activity, mycotoxin, cytotoxicity, toxicant interaction, immunotoxicity, cytokine, gene expression, gastroenteritis, enzyme induction /repression, ribosome, macrophage, biological signal transduction
DESCRIPTION (provided by applicant): Trichloroethylene (TRI) is a major environmental contaminant, is an established animal carcinogen, and is considered a "probably human carcinogen" by the National Toxicology Program and the International Agency for Research on Cancer. The kidneys are one target organ for TRI and its nephrotoxic and nephrocarcinogenic effects are mediated by metabolites derived from conjugation with glutathione (GSH). Subsequent metabolism to the cysteine conjugate S- (1,2- dichlorovinyl)-L-cysteine (DCVC) generates the penultimate toxic metabolite. It is metabolism of DCVC by either the cysteine conjugate ¿-Iyase or the flavin-containing monooxygenase that generates the ultimate reactive and toxic species. Most of the previous research that has delineated the metabolism and potential modes of action for TRI and DCVC has been performed in rodents or with tissue from rodents. While these studies, some of which have been done by the PI, have provided much useful insight, there are problems in using data obtained from rodents for human health risk assessment. This is particularly true for halogenated solvents such as TRI, because of marked species differences in metabolism, transport, and overall sensitivity to toxicity. Previous studies of ours showed that DCVC can cause both apoptosis or necrosis in primary cultures of human proximal tubular (hPT) cells, depending on concentration and time of exposure. Findings also suggested effects of DCVC on expression of proteins related to stress response and regulation of cell growth. This application uses primary cultures of hPT cells as the experimental model and will investigate the ability of hPT cells exposed to moderately toxic concentrations of DCVC to undergo repair and regeneration, the potential for DCVC to induce cell proliferation by non-genotoxic mechanisms, and the requirement for mitochondrial toxicity in the course of events leading from exposure to toxicity. The application comprises three Specific Aims. Specific Aim 1 addresses the question of whether hPT cells exposed to moderately toxic concentrations of DCVC undergo repair and regeneration. Several markers of repair will be assessed and precise conditions and potential mechanisms by which the repair and regeneration response are induced will be investigated. Specific Aim 2 will address the question of whether DCVC can stimulate uncontrolled proliferation of hPT cells. Effects on cell cycle and cell cycle signaling molecules under various conditions of DCVC exposure will be studied. Finally, Specific Aim 3 will address the question of whether mitochondrial toxicity is sufficient and necessary for DCVC-induced toxicity in hPT cells. Although previous work has shown that mitochondria are early and potently affected intracellular targets of DCVC, it is not known whether mitochondrial toxicity is an obligatory step in the progression of events that occur after DCVC exposure or whether other pathways that are independent of mitochondria can mediate renal cell injury. Achievement of these aims should build on our previous work in human kidney cells and extend it to provide a much more complete understanding of the various and complex ways in which DCVC affects the human kidney
Crisp Terms/Key Words: cell proliferation, apoptosis, DNA damage, toxin metabolism, cytotoxicity, tissue /cell culture, DNA repair, renal toxin, kidney metabolism, kidney cell, renal tubule, western blotting, human tissue, trichloroethylene, regeneration, chemical conjugate, flow cytometry, mitochondrial membrane, mitochondria
DESCRIPTION (provided by applicant): The capacity of modest inflammation to potentiate hepatotoxic responses to drugs (e.g., ranitidine) and other xenobiotic agents has been characterized in several animal models. A common finding is that both neutrophils (PMNs) and hemostasis with consequent tissue hypoxia are critical players in inflammation- potentiated hepatotoxicity. Activated PMNs kill hepatic parenchymal cells (HPCs) through the release of toxic proteases such as elastase and cathepsin G. Recently, we found that the killing of HPCs by PMN elastase is accelerated and potentiated by hypoxia. The goals of the proposal are to test the hypothesis that hypoxia and PMN proteases interact to cause HPC injury during drug-inflammation interaction and to begin to understand the molecular basis for this interaction. The influence of hypoxia on the development and dose-responsiveness of HPC killing by PMN proteases in vitro and the importance of this interaction in a drug-inflammation model in vivo will be determined. Since hypoxia-inducible factor-1 alpha (HIF-1 alpha) can initiate cell death signaling and is expressed before the onset of hepatotoxicity during drug-inflammation interaction in vivo, we will delineate its role in HPC killing during hypoxia/PMN protease interaction in vitro and during drug-inflammation interaction in vivo. Finally, since PMN proteases destroy protein disulfide isomerase (PDI), a cytoprotective hypoxic stress protein in HPC membranes, the role of PDI inactivation in elastase/hypoxia-mediated HPC death will be explored. Pharmacological, antisense oligonucleotide, conditional null and gene overexpression approaches will be employed in these studies to provide knowledge of mechanisms by which a hypoxic environment likely to occur during inflammatory conditions enhances the capacity of cytotoxic PMN proteases to damage HPCs. The results will contribute to understanding inflammatory tissue injury generally and how inflammation acts as a susceptibility factor for toxicity due to drugs and other xenobiotic agents. Public Health Relevance: Drug toxicity and many liver diseases involve white blood cells such as neutrophils operating in an oxygen-deficient tissue environment to cause liver injury. Understanding how neutrophils interact with oxygen deficiency to promote liver injury could lead to better ways to prevent or treat adverse drug reactions and other types of inflammatory liver injury.
DESCRIPTION (provided by applicant): Ultraviolet (UV) irradiation from the sun damages human skin connective tissue and causes premature skin aging (photoaging). Photoaging exists in nearly all adult individuals and is therefore a significant public health concern. In photodamaged skin, damaged connective tissue impairs normal skin function and creates a tissue environment conducive to formation of skin cancer. We have demonstrated UV irradiation reduces synthesis of type I procollagen and elevates expression of matrix-degrading metalloproteinases (MMPs), which degrade type I collagen, the most abundant structural protein in the dermis. The molecular mechanisms responsible for these skin connective tissue abnormalities in photoaged skin are far from clear. We find that the cysteine-rich protein 61 (CYR61), a secreted, extracellular matrix (ECM)-associated protein, is a novel mediator of collagen homeostasis. CYR61 is predominantly expressed in human skin dermal fibroblast, and is substantially elevated in the dermis of photoaged and acutely UV-irradiated human skin in vivo, and in UV-irradiated human skin fibroblasts. The function of CYR61 in human skin has not previously been studied. Our preliminary data indicate that CYR61 exerts dual effects on collagen homeostasis by inhibiting type I collagen production and promoting MMP-1-mediated collagen degradation, thereby causing a net deficit of dermal collagen, a prominent feature of photoaged human skin. Based on our data we hypothesize that secreted CYR61 avidly associates with EMC, and functions through integrins aV¿3 and aV¿5 to regulate collagen homeostasis. To test this hypothesis, four specific aims will be carried out: Specific Aim 1 seeks to determine the mechanisms by which UV irradiation up-regulates CYR61 expression. We will identify regulatory elements and cis-acting factors that mediate UV irradiation up-regulation of CYR61 gene transcription. Specific Aim 2 will determine CYR61 protein functional domain(s) involved in regulation of collagen homeostasis. Specific Aim 3 will determine the molecular mechanisms by which CYR61 functions through integrin-mediated pathways to regulate collagen homeostasis. Finally, Specific Aim 4 will use overexpression, knock-down, and pharmacological inhibitors to determine the role and relative contributions of multiple pathways involved in collagen and MMP-1 regulation in CYR61-mediated aberrant collagen homeostasis. Results from the proposed studies will provide a foundation of knowledge regarding the role of CYR61 in human skin.
DESCRIPTION (provided by applicant): (Descripion edited, 2/25/2005) The long term goal of the proposed research is to understand the mechanisms by which ultraviolet (UV) irradiation from the sun damages human skin and causes premature skin aging and skin cancer. Premature skin aging occurs in all persons to varying degrees as a result of normal day-to-day outdoor activities. It is especially severe in persons with high levels of sun exposure due to occupation or lifestyle. Epidemiological studies worldwide have revealed a direct connection between the incidence of skin cancer and exposure to UV irradiation. Skin cancer is the most common type of cancer in the Caucasian population of the United States; with more than 500,000 to 1,000,000 cases diagnosed each year. The annual cost of treatment in the U.S. is estimated to be between $500 million and $1 billion. These findings are directly relevant to public health care in the largest sense, yet knowledge regarding the mechanisms by which solar UV irradiation damages skin is far from complete. Ultraviolet irradiation damages human skin by at least two interdependent, but distinct, mechanisms 1) DNA damage, which results in genetic mutations that lead to cellular transformation, and 2) activation of signal transduction pathways, which strongly induce matrix metalloproteinases, and other gene products, which promote a local tissue environment conductive to cancer formation. Emerging evidence indicates that tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) is a primary driving force by which UV irradiation stimulates signal transduction pathways that induce matrix metalloproteinases. The focus of this proposal is to elucidate the molecular mechanisms by which UV irradiation increases EGFR tyrosine phosphorylation. The proposed studies will test the hypothesis that receptor-type protein tyrosine phosphatase-k (RPTP-k) specifically dephosphorylates EGFR. Reversible inhibition of RPTP-k by UV-generated oxidative stress results in increased EGFR tyrosine phosphorylation, which drives downstream signal transduction pathways. Four Specific Aims are proposed: 1) Determine regulation of EGFR tyrosine phosphorylation and signaling by RPTP-k, 2) determine substrate specificity of RPTP-k, 3) determine functional domains of RPTP-k, and 4) determine the role of co-localization of EGFR and RPTP-k in caveolin-enriched membrane rafts in regulation of EGFR tyrosine phosphorylation and signaling.
DESCRIPTION (provided by applicant): Human activity has resulted in the environmental distribution of many toxic substances, among them the heavy metals that are spread throughout our biosphere. In addition to the acute toxic effects to humans exposed to lead (i.e. in lead paint or in contaminated drinking water) there are more insidious effects of chronic exposure on the development of all organisms. Children exposed to low levels of lead have altered developmental processes, and these children develop symptoms such as hyperactivity, changes in sensory function, and changes in cognitive abilities ("IQ"). Drosophila is a promising model organism to study the effects of lead exposure during development because of (1) the sophisticated understanding of its genetics, and the ease of manipulating its genome; (2) the availability of behavioral and morphological assays sensitive to small effects of very low doses of lead. There is thought to be a great deal of variability in the sensitivity of lead exposure, and both human and Drosophila cells are thought to induce expression of "protective genes" upon exposure to lead. The hypothesis for this proposal is that one can identify some of the "protective genes" that make an organism resistant to the behavioral and developmental effects of lead toxicity using quantitative trait loci (QTL) mapping techniques combined with microarray and sophisticated genetic analyses. To test this hypothesis, Aim 1 is to map lead sensitive QTL by exposing larvae of 90 recombinant inbred Drosophila strains to environmentally relevant doses of lead, and assaying several behavioral and synaptic connection aspects that are affected by lead - such as larval locomotion, adult learning, adult locomotion, adult locomotion combined with ethanol vapor exposure, and the structure of the larval neuromuscular junction. Aim 2 is to perform DNA microarray analyses with labeled mRNA from whole larvae and adult heads from the recombinant inbred lines that show the greatest differences in lead-induced behavioral alterations, as determined in Aim 1. Aim 3 is to up-regulate, by conditional over-expression, or down-regulate, by using existing mutations and RNA interference techniques, the genes that overlap in the assays performed in Aims 1 and 2, and to determine the effects of lead on cognition, locomotion and synaptic function of these genetically altered flies. Results of these studies will identify candidates for the most important genes that are altered during lead exposure in humans, and could well lead to bioassays or treatments for heavy metal exposure at or below NOAEL and LOAEL values.
DESCRIPTION (provided by applicant): Methylmercury (MeHg) is an environmental neurotoxicant that is responsible for several massive chronic and acute poisoning events occurred in the past. Mercury pollution remains a major environmental concern for public health, particularly for populations with high-fish diet and pregnant and nursing women. This concern has been heightened due to recent reports that dietary consumption of MeHg contaminated seafood is associated with greater potential risk of neurotoxicity than we previously thought. Acute and chronic MeHg exposure disrupts sensory and motor functions and causes severe neurotoxicity in humans and animals. One of the most consistent manifestations of MeHg poisoning in humans and animals is the visual functional disturbance. This is characterized by a concentric constriction of the visual fields - the peripheral visual sensitivity is lost whereas the central vision is virtually unaffected. Corresponding to the visual deficits are region-selective pathological lesions in the visual cortex. The underlying mechanisms for these impairments remain poorly understood, although it appears that the MeHg-induced visual deficits originate in the visual cortex. MeHg-induced region-selective pathological alterations in the visual cortex are thought to be responsible for the permanent loss of the peripheral visual fields. However, visual functional disturbances often occurred in the absence of or proceeding pathological changes in the visual cortex. Thus, the visual deficits could be due to MeHg-induced temporary disruption of certain neuronal function in the visual cortex. We hypothesize that MeHg may preferentially affect synaptic function of a specific population of neurons in the visual cortex. The long-term objective of this project is to understand the cellular and molecular bases for MeHg-induced region-selective neurotoxicity in the visual system. As an initial step, the present project is designed specifically to determine if MeHg preferentially affects synaptic function of certain populations of neurons in the visual cortex. The specific aims are to determine if neurons and their associated synaptic function in a particular region or layer of the visual cortex are affected selectively by MeHg and if GABAergic responses are more sentitive to MeHg than are glutamatergic responses. This study could be the first one designed specifically to examine the chronic effects of MeHg on the central visual function. Results of this study will provide specific information about the selective neurotoxicity of MeHg in the visual system.
DESCRIPTION (provided by applicant): Astrocytes are an important component of the neuropil and their dysfunction has been associated with a variety of idiopathic and genetic diseases including Alzheimer's and Parkinson's disease and in energy deprivation syndromes such as thiamine deficiency and antimetabolite poisoning. The prevailing model of healthy astrocyte-neuron interaction is one of continuous and intimate physical contact between adjacent membranes that promotes neuronal homeostasis. While the loss of astrocytes in the neuropil is generally viewed as a negative event, we propose here that in the acute phases of intoxication loss of astrocytes may protect neurons against further injury mediated by release of adenosine. Specifically, in this proposal we hypothesize that DNB-induced oxidative stress in astrocytes induces the release of adenosine which in turn activates A1 receptors in neurons via paracrine mechanisms and self-regulates A2 receptors on injured astrocytes. Since oxidative stress is the precipitating event, the corollary to this hypothesis is that in neurons, oxidative stress converges on PI3K/ERK to regulate the activity of BCL proteins that promote mitochondrial fusion and stabilization of the cell. Additional neuronal protection is achieved via A1-mediated activation of AKT with blockage of pro-death Bcl proteins and activation of survival Bcl-proteins. Conversely, in astrocytes, activation of the A2 receptor exacerbates loss of calcium control, swelling and cell death. This hypothesis for the role of astrocytes in the protection of neurons from oxidative stress-induced cell death will be tested by addressing the following specific questions. AIM 1: Can adenosine released by astrocytes silence neurons and protect them from the effects of exposure to 1,3-DNB? Aim 2: Does A1 receptor mediated signaling through PI3K, AKT and/or ERK block death- related members of the Bcl-family of proteins in neurons? Aim 3: Is the course of mitochondrial fusion or fission determined by or dependent upon binding of Mfn1/2, Bax/Bad/Bcl-XL and Drp 1? Aim 4: Does binding of proteins that alter mitochondrial morphology also alter membrane potential and function? Dinitrobenzene (DNB) provides and excellent model of energy deprivation syndromes with selective damage to astrocytes. This experimental approach will enable dissection of the role of BCL-proteins, mitofusins and Drp-1 in coordinating the loss of mitochondrial function and may provide new insights into neuronal/glial interactions that form the foundation for pathoclisis, or selective cellular susceptibility to environmental neurotoxicants. PUBLIC HEALTH RELEVANCE Astrocytes are supporting cells in the central nervous system. Data from our laboratories show that they are a primary target of many environmental chemicals that result in dysfunction of the central nervous system. As injury to the astrocyte progresses, ATP is converted to adenosine and is released into the extracellular space where it can interact with A1 receptors on neurons (protective) and A2 receptors on astrocytes (injurious). We propose here that in the acute phases of CNS injury, loss of neuronal function (silencing) is elicited by adenosine and may spare the neuron from the deleterious effects of oxidative stress and excitotoxicity.
DESCRIPTION (provided by applicant): Methylmercury (MeHg) is an environmental neurotoxicant that causes developmental and adult toxicity. Exposure results from eating MeHg-contaminated seafood and fresh water fish. Effects of lifetime exposure to low levels of MeHg as might occur by regular seafood consumption, especially interactions between MeHg and aging, are unexplored. Previously, we demonstrated that disruption by MeHg of intracellular Ca2+i homeostasisi s crucial to earlyonset of MeHg-induced cytotoxicity. Neuronal[Ca2+]i homeostasis and synaptic function are also altered significantly during aging. The present proposal focuses on in vivo chronic lifetime exposure of animals to MeHg during beginning adulthood. The proposed studies will specifically examine whether chronic adult-onset (lifetime) exposure to MeHg accelerates cerebellar synaptic dysfunction associated with aging, ant its' sensitivity to protection by Ca2+ channel blocker treatment. The role of radial Type II astrocytes--the Bergmann cells in MeHg--induced cerebellar dysfunction will also be examinine, as these cells regulate the ionic environment at cerebellar glutamatergic synapses and their dysfunction could contribute to MeHg neurotoxicity. We hypothesize that adult exposure to MeHg enhances the severity of, or speeds up the onset of Ca2+-mediated neuronal dysfunction which has been well described in aging. An integrated set of studies using sophisticated cell imaging, single cell electrophysiological, neurobehavioral and pathological methods will test: 1) whether chronic adult-onset MeHg exposure disrupts cerebellar synaptic transmission, and to what extent these effects are brain region, or neuron-type specific; 2) to what extent the effects on Ca2+i homeostasis seen in vitro translate into established behavioral effects of adult-onset MeHg exposure in the adult or aging organism, and whether MeHg accelerates behavioral consequences of aging; and 3) whether adult-onset exposure of rats to low levels of MeHg accelerates the onset of, or severity of aging-related increased [Ca2+]I with potential effects on L-type Ca2+ channels and/or glutamate transport (or do you want this to read: involves disruption of Bergmann cell function ?). The ability of an L-type Ca2+ channel blocker to prevent, reduce or delay effects of MeHg exposure will be tested. Morphological studies will determine whether cellular and behavioral effects of MeHg during aging are accompanied by structural alterations. The proposed studies will be the first to integrate cellular mechanistic, behavioral, and morphometric effects of MeHg in a whole animal and chronic exposure model. They would also be the first to combine behavioral endpoints with cellular electrophysiology and imaging to study how a known neurotoxicant disrupts brain function. These studies are important for public health, particularly for a society with increasing life-span, because they examine a potential interaction between a well-known environmental contaminant and the aging process. PUBLIC HEALTH RELEVANCE Methylmercury (MeHg) is an environmental neurotoxicant that causes developmental and adult toxicity. One brain area affected by MeHg is the cerebellum - a region involved in motor learning and memory, as well as movement. The present proposal is designed to test if this area would be susceptible to effects of MeHg during aging.
DESCRIPTION (provided by applicant): The Harvard-Mexico Project on Fetal Lead Exposure, Risks and Intervention Strategies (FLERIS), a collaboration between investigators at Harvard University and the National Institute of Public Health in Mexico, has been a model of international teamwork and environmental epidemiology using state-of-the-art methods that won the 1999 NIEHS Progress and Achievement Award. FLERIS established three birth cohorts using similar methods that we continue to follow. In this revised competitive renewal of our R01, we propose to follow-up, collect and analyze new data and samples on all three cohorts and fully capitalize on its rich associated bank of archived data and samples to address two major themes representing novel hypotheses with critical implications for public health: (A) the potential of fetal neurotoxicant exposure to negatively impact on child behavior (aggression and attention deficit/hyperactivity); and (B) the potential for the impact of fetal neurotoxicant exposures on both cognition and behavior to be modified by gene-environment interactions involving candidate genes critical to CNS cholesterol metabolism. Our primary fetal exposure of concern will remain environmental lead exposure, because of its continuing primacy as an environmental hazard in the United States and Mexico. We have chosen specific genes because of growing evidence for the centrality of cholesterol metabolism to neurodevelopment, intriguing preliminary data pointing to cholesterol gene-lead interactions recently published by our group, and new unpublished but supportive data produced for this re-submission. We will also examine several exploratory hypotheses that attempt to develop pre-pulse inhibition as an early predictor of lead's impact on behavior and that assess the potential for measures of maternal circulating cholesterol, maternal dietary cholesterol, and infant 24S-hydroxy cholesterol (a novel plasma biomarker of CNS cholesterol) to modify the lead-gene interactions with respect to cognition and behavior. Finally, we will use our data to compare the relative impacts of prenatal with postnatal lead exposure. This research promises to provide key insights into mechanisms of neurotoxicity, individual susceptibility, and both behavior and cognition as toxic endpoints.
DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a progressive, degenerative and fatal neurological disorder which involves decreased skeletal muscle function as a result of loss of upper and/or lower motor neurons. Clinical signs of ALS include skeleta muscle weakness, muscle cramping and fatiguing, slurred speech and difficulty swallowing. ALS typically presents later in ife. Cellular degeneration in ALS occurs specifically in the nervous system. Two forms of ALS have been identified. The vasi majority of cases of ALS are referred to as sporadic (SALS), in which the etiology of the disease is unknown, but there is no family history of ALS. Between 5-12% of ALS cases are referred to as Familial ALS (FALS). Some of these appear to be due to a number of identified, inherited mutations in superoxide dismutase-1 (SOD1) the gene which encodes Cu/Zn containing SOD. How ALS causes motor neuron degeneration is as yet unknown, although several postulated mechanisms are thought to contribute to ALS. One major hypothesized mechanism is glutamate mediated excitotoxicity, perhaps due :o impaired astrocytic uptake of glutamate. Following excitotoxicity, elevations of intracellular [Ca] ([Ca]|) with subsequent mitochondrial damage and generation of reactive oxygen species occur; all of these could contribute to motor neuron degeneration. Contribution of environmental exposure factors to the etiology of ALS has been repeatedly hypothesized, bul no specific environmental exposure factors have definitively been linked with ALS. Among the environmental toxicants )roposed as possible contributors to the etiology of ALS include neurotoxic heavy-metals, particularly Hg2+, Pb2* and Cd2* This R21 proposal is designed to test the hypothesis that exposure of motor neurons to methylmercury (MeHg)-predisposes them to excitotoxic damage. In a number of types of neurons, MeHg increases [Ca];, disrupts mitochondrial function,, and causes release of vesicular glutamate from nerve endings. Any of these actions could contribute to enhanced sensitivity of motor neurons to subsequent environmental exposure damage, or in motor neurons having as yet undetermined genetic predisposition to ALS. A transgenic mouse line overexpressing the human mutant SOD1 (G93A) will be used to compare fleets of MeHg in a commonly accepted animal model of FALS. Proposed studies will involve fluorescent measurements of changes in [Ca]h glutamate release and mitochondrial Ca2+ in hypoglossal motor neurons in slices of brainstem of SOD1 mice following chronic MeHg exposure postnatally. The ability of MeHg to exacerbate the onset of ALS-signs will be examined using a rotarod test to determine if the onset of ALS-like phenotype is faster with MeHg. Results of the proposed exploratory study should provide evidence for or against environmental exposure to MeHg as a. possible contributor to motor neuron degeneration during ALS-particularly in susceptible or genetically predisposed populations.
DESCRIPTION (provided by applicant): The overall objective of this research is to understand the contribution of the MAPK and NFkB pathways in the etiology of inflammation of extra-placental gestational membranes. Understanding the etiology of inflammation in gestational membranes is important because of the strong link between inflammation-associated release of cytokines and prostaglandins in preterm birth and other adverse birth outcomes. The critical knowledge gaps addressed in this research are: 1) initiation of inflammation in gestational membranes by noninfectious stimuli such as environmental pollutants, 2) activation of the MAPK pathway by infectious and noninfectious stimuli, and 3) cross-talk and amplification of cytokine and prostaglandin production by positive feedback on the MAPK and NFkB pathways. The overarching hypothesis is that infectious and noninfectious agents stimulate increased release of pro- inflammatory cytokines and prostaglandins through activation and positive feedback of the MAPK and NFkB signal transduction pathways. This hypothesis will be tested using human gestational membrane cell and tissue explant cultures exposed to the bacterial toxin lipopolysaccharide (LPS) as a model infectious stimulus and the environmental pollutants polybrominated diphenyl ethers (PBDEs) and p,p'-DDE as model noninfectious stimuli. The Specific Aims are to: 1) identify the cell targets in human gestational membranes for PBDE-stimulated release of proinflammatory cytokines and prostaglandins; 2) determine whether PBDEs stimulate release of pro- inflammatory cytokines from gestational tissues at relevant concentrations; 3) delineate the roles of the NF-:B and MAPK pathways in cytokine and prostaglandin synthesis in human gestational membranes following stimulation with infectious and noninfectious agents; and 4) determine whether prostaglandins and cytokines interact in a positive feedback manner through the NF-:B and MAPK pathways to amplify production of prostaglandins in gestational membranes in response to infectious and noninfectious pro-inflammatory stimuli. Results from this research will increase our understanding of the causes of inflammation in gestational membranes and, as such, may contribute to improved pregnancy outcomes through enhanced strategies for prediction and prevention of risks for preterm birth and other associated adverse birth outcomes. Reducing preterm births is a Health People 2010 objective. PUBLIC HEALTH RELEVANCE: Knowledge of pollutant contributions to preterm birth is scarce, yet epidemiologic study of pollutant risks to pregnancy is difficult, expensive and time-consuming. Given the thousands of chemicals to which pregnant women may be exposed, a strategy is required for selection of exposures for epidemiologic analysis. By using PBDEs and DDE as model toxicants to investigate biologic plausibility, the proposed experiments may provide a rational approach for selection of pollutants for further study. Moreover, the results from this research may increase understanding of the causes of inflammation in gestational membranes and, as such, may contribute to improved pregnancy outcomes through enhanced strategies for prediction and prevention of risks for preterm birth.
DESCRIPTION (provided by applicant): Prostate Cancer is a slow growing disease that likely involves a series of environmental insults resulting in accumulated DMA damage eventually leading to overt carcinogenesis. DNA adducts are one of the few biomarkers for exposures directly related to cancer that can be quantified in human cells and a reliable measure of biologically effective dose for known carcinogens such as polycyclic aromatic hydrocarbons (PAH) and 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP). Epigenetic markers are emerging as important in determining the extent of prostate carcinogenesis. Recent studies suggest that DNA adduct formation and aberrant gene promoter hypermethylation may be related elements in environmentally-induced carcinogenesis. Most research done with respect to DNA adducts, promoter hypermethylation and prostate cancer has focused on cells harvested from patients with prostate cancer or pre-malignant lesions. While these studies have been instructive, a clearer picture of the interconnection and risk associated with DNA adduct formation and epigenetic changes in prostate can only be gained from studies of prostate tissue captured before the onset of disease. At the Henry Ford Health System, we have characterized and have access to a racially diverse cohort of over five thousand men without prostate cancer from whom benign prostate specimens were surgically removed between 1990 and 2002. We plan to expand this cohort through 2006, and will follow-up cohort members for incident prostate cancer diagnoses through 2010 to achieve a desired study sample size of 800 matched case-control pairs. Building on findings from our initial funding period that characterized determinants of PAH- and PhlP-DNA adducts in the prostate cells of men with prostate cancer, in this competing continuation we seek to better understand the temporal relationship between DNA adducts and other epigenetic changes in the benign prostate and later prostate cancer development. To achieve this objective, we plan to conduct a nested case-control study of prostate cancer that will: 1) determine whether PAH- and PhlP-DNA adducts are predictive of later prostate cancer development after adjusting for other possible confounders; 2) determine in a multivariable model how aberrant gene promoter DNA methylation affects the association between PAH-and PhlP-DNA adducts and prostate cancer; and 3) determine whether DNA adducts in the benign prostate are associated with the level of expression of the p53 and p21waf/cip1 tumor suppressor genes in prostate tumors of men who develop prostate cancer.
Crisp Terms/Key Words: p53 gene /protein, oncoprotein p21, gene environment interaction, DNA damage, DNA methylation, cancer risk, neoplasm /cancer epidemiology, prostate neoplasm, neoplasm /cancer genetics, chemical related neoplasm /cancer, mathematical model, human tissue, carbopolycyclic compound, adduct, environment related neoplasm /cancer, clinical research, chemical carcinogen
DESCRIPTION (provided by applicant): In Phase I, we have developed a novel approach to the analysis of toxicogenomics data based on functional categorization and signature networks. The method enables identification of pathways and biological networks most different between gene expression response to drug action, and it can be applied for categorization of molecular profiles by toxicity categories. We have also functional profiling on a large dataset of hepatotoxic compounds from CEBS database. In Phase II, we propose to formalize the new approach in algorithms and build a semi-automated module for generation of signature networks specific for a toxicity type. We will also build a reference database of quantitative functional descriptors for toxic categories which can be used for categorizing of molecular profiles for novel compounds. We will develop a workflow for functional analysis of toxicogenomics datasets and a reporting protocol which sponsor companies can use for voluntary submission of toxicogenomics data to FDA and the reviewers for evaluation of the submitted data. Finally, we propose to build a novel integrated platform for functional data mining of toxicogenomics data and reporting, MetaTox. MetaTox will include the manually curated database of human biology created at GeneGo, a general datamining toolkit (networks, pathways, cellular processes, disease and toxicity categories), pre-processed toxicogenomics data from public domain, and the tools created in the scope of this project (signature networks module and the database of functional descriptors for toxicity categories). In Phase II, we propose to complete the set of tools and workflows for functional analysis of toxicogenomics data. This will include a novel module for generation and comparison of signature networks for different toxic categories, matrix of quantitative functional categories and a new toxicogenomics platform MetaTox
DESCRIPTION (provided by applicant):
The objective of this proposal is to develop a curricula of role specific online e-Learning courses that meet the needs of a diverse workforce of Hazardous Material workers in the transport modalities of: highway, marine, air, rail, and International. This specifically relates to the goals of the Worker Education Training Program and Health Worker 2010. Hypothesis: Online e-Learning can improve mandated workforce Hazardous Material training by increasing individualization, using the web to simplify dissemination, and shortening time-to-competence, while saving costs. Phase I developed and implemented a highly interactive, e-Leaming course, HazMat Truck, and supporting systems. Experts and workers have favorably evaluated the streamlined approach, time-savings, and opportunity to practice designed into the course. Phase II proposes to broaden that study in number and occupation and to develop a curricula of courses with interactivity that addresses the needs of workers in all transport modes. Once finalized, courses will be translated to Spanish and test-marketed. Phase III will sell or license the courses to companies required to provide training combined with the unique delivery system that specifies exactly the right course to take, maintains training records, and sends refresher reminders. Technological innovation will provide: (1) a curriculum of up-to-date, interactive courses that meets diverse needs, (2) a protocol that matches competency needs to course content, (3) analysis of the efficacy of e- Learning for this population, (4) a customization database that can add state, local, and institution specific requirements to the generic courses. The potential commercial outcome will benefit workers and companies. Millions of people in the US, federally mandated to receive workplace Hazardous Material training, often they do not receive it due to time, travel, or language. These courses will solve that. Companies responsible for delivering yearly training could save $1.4 billion per year in the US and ensure valid, up-to-date training, available anytime, anywhere.
DESCRIPTION (provided by applicant): Space-Time Clustering of Testicular Cancer Using Residential Histories Abstract The primary objective of the proposed research project is to generate insights concerning the etiology of testicular cancer by conducting a large, population-wide case-control study in Denmark investigating space- time clustering of cases and controls using residential histories. Testicular cancer is the most common cause of cancer in men aged 15-34 yet relatively little is known about its etiology. The established and presumptive risk factors, taken as a whole, account for only a small proportion of the total cases of testicular cancer, and novel techniques are needed to solve this public health enigma. Our research team has recently developed Q-statistics and Space-Time Information System (STIS) technology that enable space-time cluster analyses. Other methods for analyzing cancer clusters typically ignore residential mobility, and almost exclusively work with static spatial point distributions of place-of-residence at time of diagnosis or time of death. In addition, few spatial techniques adequately account for known risk factors and covariates. Our approach addresses each of these needs by utilizing the residential history of the participants represented as a life-line, and thus evaluates space-time clustering at any moment in the life-course of the residential histories of the cases relative to the residential histories of the controls. In addition, in place of the widely used (but often inappropriate) null hypothesis of spatial randomness, Q-statistics can incorporate each individual's probability of being a case based on his/her risk factors and covariates. This project will apply the innovative Q-statistics and STIS technology to identify spatial clustering of testicular cancer by comparing the residential histories of the cases with those of the controls. The proposed research will select testicular cancer cases (3100) from the nation-wide Danish Cancer Registry (diagnosed in 1994-2003) and controls (3100, matched on age) from the general population. The cases and controls will be linked with residential history information available in the Danish Central Population Registry and Q-statistics will be implemented to examine clustering. Local authorities and registers at the Danish Environmental Protection Agency will be asked to identify possible patterns of environmental contamination surrounding the most significant clusters to generate hypotheses about environmental causes of testicular cancer. Future research will address such environmental hypotheses by collecting biomarkers and modeling environmental contaminants within an epidemiologic framework. This research will, for the first time ever, allow epidemiologists to assess space-time clusters of testicular cancer using detailed residential histories, with the intended purpose of generating fresh hypotheses about potential etiologic factors associated with testicular cancer to be investigated in future studies. Space-Time Clustering of Testicular Cancer Using Residential Histories Relevance The scientific innovations from this research are expected to dramatically improve our understanding of testicular cancer, the most common type of cancer in men aged 15-34. This research will enable environmental and spatial epidemiologists to investigate spatial clusters of testicular cancer by comparing residential histories of cases with residential histories of controls, with the intended purpose of generating fresh hypotheses concerning the etiology of testicular cancer.
DESCRIPTION (provided by applicant)
The goal of this Mentored Research Scientist Development Award is to support the Principal Investigator to gain the research knowledge, skills and experience to conduct environmental, gerontological and genetic epidemiology studies. This award will promote the candidate's ability to achieve the long-term goal of developing into an independent investigator. The proposed career development plan aims to build on the candidate's prior research experience in environmental epidemiology with new training in genetics, epidemiology of aging, and neurotoxicology. The scientific goals of this project are to understand how long term environmental exposures to lead and air pollution affect age-related pathological changes, namely, depressed cardiac function, and two novel outcomes that have been relatively little studied in environmental health, age-related cataract and hearing loss. In addition, the project aims to identify factors that impact susceptibility to such pollutants in an aging population. These health endpoints are leading chronic health conditions experienced by the older adults, but the biological mechanisms by which pollution exposures may impact these age-related conditions are poorly understood. The candidate will not only examine independent effects of lead and traffic-related particles, but focus on genes involved in the pathway of iron regulation metabolism which may modify the lead and particle responses. The investigator will also examine if the associations between pollutants and age-related diseases are modified by dietary intake of antioxidants (vitamins C and E, carotenoids, and cruciferous vegetables) and omega-3 fatty acids. In order to apply the candidate's past research background in these research aims in the field of gene-environment interaction and epidemiology of aging, additional training and mentorship is necessary. The proposed career development plan includes working with established experts in metals and air pollution epidemiology, genetic epidemiology, gerontological epidemiology, neurotoxicology, ophthalmology and otolaryngology, and is enhanced by didactic coursework, laboratory training and attendance in seminars and national/international meetings. This proposal will take advantage of the data and archived samples from a large, well-phenotyped, on-going, longitudinal cohort of community-residing elderly men, the Normative Aging Study, and for some of the specific aims, a sub-sample of the Nurses' Health Study will be utilized. Relevance: As the aging population grows, the need to better understand the causes of age-related pathological changes is required, but little is known about the impacts of environmental pollutants on such age-related diseases. This project will identify which sub-population in terms of genetic polymorphisms and nutrient intakes is more susceptible to environmental exposures to lead and air pollution, and ultimately suggest preventive public health strategies to improve the quality of life in the aging population.
DESCRIPTION (provided by applicant):
Exposure to diesel exhaust, a significant source of particulate matter (PM) in urban residential environments, adversely effects respiratory health of asthmatics and augments allergic sensitization to allergens. Yet much remains unknown about which aspects of diesel exposure are driving the observed health effects, the effect of diesel exhaust exposure in combination with other asthma triggers, and whether any of the effects of diesel are modifiable on an individual basis. The Michigan Center for the Environment and Children's Health (MCECH) recently conducted an integrated ambient PM exposure assessment, health effects epidemiologic study, and home intervention to reduce indoor allergens among asthmatic children in Detroit. Fluctuations in lung function associated with PM2.5 or PM10 exposure were more prominent in children who were allergic to cockroach compared to those who were not allergic. These data suggest a model in which PM, specifically that derived from diesel exhaust, and indoor allergen exposures interact synergistically to increase pulmonary inflammation in asthmatic patients. To test this hypothesis, the investigators propose these specific aims:
1) Determine whether the fraction of ambient PM arising from diesel exhaust determines pollution-related respiratory health effects in children with asthma in an inner-city environment. Statistical associations between ambient elemental carbon (EC), a marker for diesel exhaust, and acute respiratory outcomes (lung function, symptoms, bronchodilator use, acute care visits) will be investigated in children with asthma.
2) Determine the potential interactions between the effects of ambient diesel exhaust (as traced by EC) and exposure to allergens and environmental tobacco smoke (lETS). Interactive effects between EC and household exposure to indoor allergens, and ETS exposure, on health status will be investigated in children with asthma.
3) Determine the causal relationship between indoor allergen exposure and heightened sensitivity to air pollutants by performing an intervention designed to reduce indoor allergen exposure. A new integrated health effects study and prospective randomized trial of home environmental intervention will be conducted with extensive spatial and temporal assessment of ambient diesel exposure, assessed by EC concentration and ultrafine particle number, and health outcomes. The investigators will compare the acute air pollutant-associated fluctuations in asthma health status in the intervention group to that in a control group. They will also investigate associations between exhaled hydrogen a biomarker of asthma activity, and diesel exhaust exposure.
DESCRIPTION (provided by applicant): Enzymes utilize organic radicals to catalyze a variety of important metabolic reactions. The overall goal of this research is to delineate the mechanistic details of radical generation and control by these enzymes. This research focuses on three radical enzymes: benzylsuccinate synthase (BSS) and its activating enzyme (AE) in the K99 phase, and spore photoproduct lyase (SPL) in the ROD phase. The later two enzymes belong to the radical SAM superfamily, which utilize S-adenosylmethionine (SAM) coupled by a unique [4Fe-4S] cluster to generate the reactive organic radicals. BSS, found in bacteria like T. Aromatica, converts toluene to benzylsuccinate by a mechanism involving protein-based glycyl radical to initiate the toluene anaerobic biodegradation process. This research is of significance due to the fact that toluene and its related compounds comprise a major category of pollutants with neuronal and cancer-promoting toxicity. To generate the glycyl radical, an activating enzyme (AE) is needed, which oxidizes the glycine residue using a S'-deoxyadenosyl radical generated, in turn by reductive cleavage of SAM with the electron provided by a [4Fe-4S] cluster. To investigate this BSS-catalyzed toluene bioremediation process, biochemical, spectroscopic, and mutagenic studies of both BSS and BSS-AE will be pursued. The specific aims include the investigations of enzyme kinetics, the functions of different [4Fe-4S] clusters in BSS/BSS-AE, and the roles of different organic radical intermediates during the catalysis. SPL exists in the spores of bacteria such as B. subtilis, and repairs unique T-T crosslink 5-thyminyl-5, 6- dihydrothymine (commonly called spore photoproduct, SP) formed upon UV irradiation. SPL adopts a "direct reverse" strategy to repair SP, which involves neither removal nor replacement of bases or nucleotides. It thus represents a unique DNA repair pathway in Nature. To understand the SPL mediated DNA repair reaction, chemical, kinetic, spectroscopic, and mutagenic methods will be employed. The objectives include: investigating the SP repair in a wide range of DNA secondary structures, probing the reaction mechanism by SP analogues (mechanism-based enzyme inhibitors), and examining the kinetic isotope effects and reaction reversibility. In addition, the redox potential of the [4Fe-4S] cluster will be determined and the influence of SAM and key amino acids to the redox potential will be investigated.
DESCRIPTION (provided by applicant)
Ozone (O3) exposure associates with exacerbation of asthma and altered lung function in adults and children, and mortality. Over 50% of the United States population live in regions where O3 concentrations approach or exceed the National Ambient Air Quality Standard of 0.12 parts per million (ppm). The candidate previously identified the innate immunity gene toll-like receptor 4 (Tlr4) as a candidate susceptibility gene for 03-induced lung hyperpermeability and inflammation. C3H/HeOuJ mice (Tlr4 sufficient) are significantly more susceptible to O3-induced hyperpermeability and inflammation compared to co-isogenic C3H/HeJ mice (Tlr4 dominant negative mutation). However, the downstream effector mechanisms for TLR4-mediated responses are still unclear. The overall objective of this proposal is to determine the mechanisms by which TLR4 mediates O3 induced lung inflammation and hyperpermeability. The proposed studies will use a multidisciplinary approach using molecular biology, genetics, and pharmacological techniques in an in vivo animal model to address the following specific aims: 1) examine the influence of strain background on the role of Tlr4 in O3-induced lung hyperpermeability and inflammation using mice that are Tlr4 dominant negative and Tlr4 transgenic mice; 2) determine if immediate signaling events downstream of Tlr4 are altered in response to O3 exposure in Tlr4 deficient or Tlr4 over-expressed mice and to evaluate the downstream cytokine profiles for these strains to determine if strain background can modulate the types of cytokines produced; 3) investigate the downstream mechanisms by which Tlr4-dependent pathways regulate O3-induced responses by verifying the importance of candidate genes identified from Affymetrix global gene arrays in vivo using molecular approaches and utilizing genetic (knockout mice) and pharmacologic methods to investigate specific candidate genes previously identified by the microarray approach. This proposal will enhance the understanding of the mechanisms of O3-induced lung inflammation and injury by the identification of novel pathways regulating O3 susceptibility. These novel pathways may provide preventive strategies for those individuals susceptible to O3.
Crisp Terms/Key Words: toll like receptor, microarray technology, genetic susceptibility, gene environment interaction, animal genetic material tag, lung injury, respiratory epithelium, ozone, cytokine, inflammation, vascular endothelium permeability, genetic strain, biological signal transduction, genetically modified animal, laboratory mouse, air pollution
DESCRIPTION (provided by applicant):
The Multidisciplinary Training Program in Environmental Toxicology (MTPET) described in this application produces scientists having a base knowledge in environmental toxicology coupled with research expertise gained in a departmentally-based, biomedical science graduate program. Predoctoral trainees must meet the full Ph.D. requirements of their "home" department and complete the coursework, research and interactive aspects of the MTPET administered through the Institute for Environmental Toxicology (lET). The degree awarded recognizes the dual nature of the training by listing the department-environmental toxicology (e.g., Ph.D. in "Biochemistry and Molecular Biology- Environmental Toxicology"). Graduates of the program are well equipped to conduct research and interact with other scientists in the course of solving complex environmental toxicological problems that require collaborative, multidisciplinary approaches.
Fifteen training faculty conduct predoctoral training in five departmental Ph. D. programs (Pharmacology and Toxicology, Biochemistry and Molecular Biology, Food Science and Human Nutrition, Zoology, Cell and Molecular Biology). Added to the department-based education and environmental toxicology research training in participating departments are didactic, toxicology-oriented courses and other requirements of the MTPET. This coursework and less formal multidisciplinary interactions and activities provided by the lET and MTPET impart a wider scope of knowledge than is available within individual departmental programs. Research topics for trainees are available in mechanisms-related toxicology encompassing various organ systems (e.g., hepatic, immune, endocrine, neuronal, respiratory), carcinogenesis, and food safety. There is an integrative biology emphasis to the research training, which encompasses whole animal, cell-based, molecular and genomic methodologies to understand mechanisms of toxicity and factors governing susceptibility. Postdoctoral trainees conduct research in the laboratory of one (or more) of the training faculty and gain additional environmental toxicology experience through participation in lET and MTPET activities and courses.
This application is for support of six predoctoral and three postdoctoral trainees, thereby continuing a highly effective multidisciplinary training program which mixes formal and informal approaches to prepare graduates to make significant contributions to the field of environmental toxicology.
DESCRIPTION (provided by applicant)
This Training Grant Program (TGP) provides interdisciplinary research training in mechanistic toxicology with applications to human disease prevention. Support is requested for 6 predoctoral and 2 postdoctoral positions. Qualified applicants must demonstrate motivation for careers in toxicology research. Predoctoral applicants must have excellent backgrounds in biological and physical sciences and mathematics. Postdoctoral fellows must have the Ph.D., M.D., DVM, or other appropriate doctoral degree. The TGP is based in the Department of Environmental Health Sciences (EHS), which has a distinguished history of graduate training in toxicology. The curriculum provides a rigorous academic foundation for predoctoral students in basic biomedical sciences, biostatistics, epidemiology, and mechanistic toxicology. Interactions among Program participants occur through core courses, weekly seminars, dissertation committees, collaborative research, and an annual research symposium. Trainees complete independent research projects that illuminate a mechanistic basis for environmental determinants of disease. The TGP faculty has an exemplary record of funding, publications, training, and leadership in scientific societies and panels. Mentors include those with laboratories equipped for contemporary research training from the molecular to the organismal level. In addition, mentors in human exposure assessment, biomarker development, and environmental epidemiology provide opportunities for trainees to do translational research relating exposures to human health. Trainees publish their work in peer-reviewed scientific journals and are prepared for ultimate leadership positions in academia, industry, and government. A Steering Committee advises the Director and Associate Director on the budget, operating procedures, selection, and continuing review of trainees and mentors. An external Review Board reviews the TGP annually to make recommendations for continual improvement. Consultants provide advice about minority recruiting and applications of research to human populations. The University of Michigan furnishes a premier multidisciplinary research environment for training modern toxicologists. Strong institutional support for the TGP is contributed by the Department of EHS, School of Public Health, and the Rackham School of Graduate Studies, enriching the external support provided by NIEHS and ensuring an effective Training Program.
DESCRIPTION (provided by applicant): Vitamin D deficiency is much more common in African Americans than whites. The prevalence of elevated parathyroid hormone (PTH), typically a consequence of depressed vitamin D levels and/or low calcium intake, is also high in African Americans. Obesity, which disproportionately affects African Americans (especially women), has also been linked to an excessive prevalence of vitamin D deficiency and elevated PTH. However, maintenance of serum calcium concentrations by chronic PTH elevations has known deleterious physiological effects within the vasculature and myocardium such as vasoconstriction, activation of fibroblasts, insulin resistance, dyslipidemia, fat deposition and down regulation of endothelial nitric oxide - all of which plausibly contribute to elevated blood pressure (BP)and vascular and pressure- sensitive target organ injury, weight gain, dyslipidemia, and glucose intolerance. We propose a study in ~ 65 healthy, normotensive African Americans enrolled in the NIH-funded ONOSS study to examine the following before and after a 6 week period of dietary sodium supplementation: Aim #1: determine blood pressure (BP)(cuff and ambulatory 24 hour), arterial stiffness (AS), peripheral vascular resistance(PVR) and nitric oxide (NO)production and their relation to circulating levels of 25-OH vitamin D (25-OH D) and PTH at baseline; Aim #2: determine the relationship of baseline 25-OH D and PTH levels with subsequent changes in BP, AS, and PVR after dietary salt loading; Aim #3:Determine the relationship of the change in NO metabolites and stimulated NO production in platelets to changes in BP, AS and PVR after dietary salt loading; Aim #4: Determine the association of baseline 25-OH D and PTH levels with baseline levels of circulating markers of oxidative stress (total isoprostanes, nuclear factor kappa beta) and free radicals (nitrotyrosine, dityrosine, chlorotyrosine), and in turn, link circulating markers of oxidative stress to changes in BP, AS, PVR, urinary NO metabolites, and platelet production of NO after dietary salt loading Relevance: Vitamin D deficiency and secondary increase in PTH are common, particularly amongst obese persons and African Americans. They both have vascular and physiological effects that lead to the excessive prevalence of elevated BP, vascular and pressure-related target-organ injury, endothelial dysfunction, and salt sensitivity in African Americans. It is important to understand the role of vitamin D deficiency and prolonged elevation of PTH to the abnormal physiology that likely contributes to common cardiovascular complication since vitamin D supplementation is affordable, relatively non-toxic, and is available in oral formulations.
DESCRIPTION (provided by applicant) The consequences of human exposure to environmental and occupational toxicants are a global issue. Over time, the field of toxicology has come to recognize the relationship between chronic low dose exposure, and the development of disease. With the emergence of molecular and cellular biology, recombinant DNA technology, bioinformatics, and molecular genetics, biomedical science has become more complex and interdisciplinary. Unique opportunities exist to relate environmentally caused disorders to genetic, biochemical and molecular mechanisms. Therefore, it is important to train current and future scientists in the technologies of today's science, and give them the scientific foundation that will enable them to use the technologies to address environmental health issues. The Institute of Environmental Health Sciences (IEHS) is a free-standing unit within the organizational structure of Wayne State University with a focus on molecular, cellular, and genomic approaches to the study of toxicant effects. As the headquarters of a NIEHS P30-supported Environmental Health Science (EHS) Center, the IEHS functions as a focal point for stimulating, developing and coordinating instruction in toxicology, and studying the relationship between environmental factors and human disease. The IEHS is also the headquarters of an interdisciplinary pre-doctoral program in Molecular and Cellular Toxicology. The 11 faculty associated with this training program are drawn from the IEHS and the EHS Center. This T32 grant will focus on the training of 2-predoctoral students in the Molecular and Cellular Toxicology Program. The training of students selected from this interdisciplinary graduate program will be augmented by a 2-3 year appointment to the NIEHS-sponsored training grant. These students will receive intensive instruction such that they: 1) are versed in the principals of toxicology but recognize the cross disciplinary nature of the field; 2) gain expertise with many of the contemporary techniques and technologies used in the life sciences; and 3) recognize and appreciate the complex relationships between environment, genetics/genomics, susceptibility to toxicants, and the development and progression of human disease. The overall goal of the predoctoral program in Molecular and Cellular Toxicology is to develop independent scientists who are well prepared for environmental health research, and equipped to perform competitive research using contemporary concepts, approaches and the technologies of molecular biology, cell biology, genomics and genetics. It is envisioned that students with such training will be better equipped to pursue postdoctoral research at major research laboratories throughout the United States.
DESCRIPTION (provided by applicant)
UAW seeks 5-year funding to train 6,232 participants in 16 curricula for a total direct cost of $4,717,801. This builds on a 15-year effort that trains employees to respond to industrial emergencies and to handle hazardous waste, the University of Michigan evaluates the impact of the training on safety and health. The primary target will be approximately 2,600 smaller units with about 260,000 UAW members. Most are in the automobile, metalworking and transportation equipment sectors. In addition, there are public sector UAW members in waste treatment and transportation. The goal is to reduce illnesses and injuries through hazard recognition, prevention of chemical releases, improved programs and work practices. Objectives include, employing peer trainers with participatory pedagogy and demonstrating their impact on safety and health. The applicant wishes to promote implementation of their model programs beyond their membership.
Specific Aim 1 is to conduct, a) 24- and 40-hour Industrial Emergency Response (IER) courses; b) awareness training in IER, HazMat, and pollution prevention; c) 16-hour, trainings for joint hazardous, material committees; d) Advanced Training Technologies (ATT) modules; e) trainings for joint health and safety committees; f) Operations Level HazMat Refresher; and g) train-the-trainer programs. Aim 2 is to develop new curricula in, a) Tech-level HazMat Refresher, b) Critical Thinking, c) module for forklift operators and shippers/receivers, and d) Small Group Activity Method (SGAM) Instructor Guide. Remaining Specific Aims are to, 3) revise and expand curricula on Pollution Prevention and Sentinel Events; 4) continue to identify high-risk worksites and target work assignments for delivery of training; 5) expand utilization of worker trainers (Local Union Discussion Leaders [LUDLs]) in training delivery; 6) further expand the role of the LUDLs in curriculum development and program evaluation; 7) update instructor guides for SGAM and for the UAW 40-hour IER Technician Level manual; 8) participate in a multi-grantee project to diffuse training innovations such as the sentinel event curriculum; 9) further develop the worker-based evaluation component launched with the: SREP project; 10) continue partnerships with community groups and develop new community partnerships; 11) assure training quality by monitoring trainee perceptions by conducting assessments of new curricula; 12) evaluate the long-term impact of 24 and 40 hour IER training; 13) assess the effectiveness of interventions in changing unsafe workplace communities of practice and the effect of training venues on training outcomes; and 13) ensure the development of staff in competencies related to grant purposes through professional training.
DESCRIPTION (provided by applicant)
The prevalence of obesity, a major risk factor for four of the ten leading causes of death (cardiovascular disease, diabetes, dietary cancers, and stroke), has risen dramatically over the past 20 years in the United States. In neighborhoods with few economic resources, aspects of the built environment may be less conducive to physical activity and healthy diets, placing residents disproportionately at risk. The growing health burden of obesity and co-morbidities highlight the need to identify effective measures of the means by which the built environment influences health, as well as effective interventions to create healthier environments. The longitudinal study proposed here will contribute to both of these goals. Specifically, the proposed initiative is to: 1) Assess independent and collective scientific contributions of five methods of assessing characteristics of the built environment (measures of accessibility; mapping; typologies of neighborhood characteristics; observation; and residents' perceptions) for understanding the means by which the built environment influences behavioral and biological factors associated with obesity and related co-morbidities among African American, Hispanic and white residents of Detroit; 2) Develop and implement additional components of a multilevel, multi-site intervention that incorporates modifications of the built environment and that builds on ongoing social and behavioral approaches to promote physical activity and access to healthy foods in eastside, northwest and southwest Detroit; 3) Conduct longitudinal analyses to evaluate the independent and cumulative effects of modifications of the built environment, alone and in conjunction with multilevel, multi-site social, informational and behavioral approaches to promote physical activity and access to healthy foods among African American, Hispanic and white residents of eastside, northwest and southwest Detroit; and 4) Disseminate knowledge gained about the implications of changes in the built environment alone, and in conjunction with behavioral and social interventions, for behavioral and biological indicators of obesity and related co-morbidities to community members and to local, regional and national decision makers.
DESCRIPTION (provided by applicant)
Estrogenic endocrine disruptors (EEDs) are a group of structurally diverse compounds that include pharmaceuticals, dietary supplements, industrial chemicals and environmental contaminants. They can elicit a number of adverse health effects such as hormone dependent cancers, reproductive tract abnormalities, compromised reproductive fitness, and impaired cognitive abilities. In order to fully assess the potential adverse effects of synthetic and natural EEDs, a more comprehensive understanding of their molecular, metabolic, and tissue level effects is required within the context of a whole organism. This collaborative proposal will elucidate the pathways, networks and signaling cascades perturbed by EEDs using the complementary multidisciplinary expertise of its team members in the areas of toxicology, molecular biology, endocrinology, multinuclear NMR spectroscopy, data management and advanced data analysis. The comparative effects of ethynyl estradiol (EE), genistein (GEN), and o, p'-dichlorodiphenyltrichloroethane (DDT) on metabolite levels will be assessed in urine, serum and liver extracts by multinuclear (i. e., 1H, 13C, 31P) NMR spectroscopy, and complemented with histopathology examination and gene expression data from ongoing microarray studies in both mouse and rat models. All data will be stored and archived in dbZach, a MIAME-compliant toxicogenomic supportive database that facilitates data analysis, the integration of disparate data sets, the exchange of data between investigators, and the deposition of data into public repositories. Advanced statistical approaches, modeling and data integration tools such as neural networks, data fusion, and Baysean inference will be used to fuse these disparate data sets in order to elucidate the conserved biological networks that are of importance in response to endogenous estrogens. Moreover, EED perturbed pathways associated with elicited effects will be further defined. Results from these studies will not only further define the physiologic and toxic mechanisms of action of estrogenic compounds but will also demonstrate the synergy of fusing complementary microarray, metabolomic and histopathology data into a comprehensive integrative computational model. This approach will also demonstrate the ability to maximize knowledge extraction from all disparate data available within the proposed innovative data management system when used with the advanced information tools that will be developed.
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