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Record Count: 17
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DESCRIPTION (provided by applicant): Hexavalent chromium (CrVI) is a toxic DNA-damaging agent with a well-documented exposure in a large number of occupations, and it is a common environmental contaminant. Cr(VI) is listed by the ATSDR and EPA as one of the top 20 high priority toxic agents. The final oxidative form of Cr in biological systems is Cr(lll) that produces several stable DNA adducts. We have recently found that Cr(III)-DNA adducts are one of the major causes of mutagenicity of Cr(VI). Our new data indicate that Cr-DNA adducts also play an important role in toxicity of Cr(VI). Toxic responses to Cr-DNA adducts were strongly dependent on the presence of a small group of proteins that bind to Cr-damaged chromatin. This proposal is designed to test our working hypothesis that cytotoxic effects of Cr-DNA adducts are caused by the formation of secondary DNA lesions generated as a result of the recognition and processing of adducts by damage sensory proteins. Biochemical approaches and cellular models with downregulated levels of damage-processing proteins will be used to gain evidence supporting the proposed hypothesis. We constructed a series of the retroviral siRNA-encoding vectors, which will allow us to examine the role of various proteins in the cytotoxic responses in the target primary human bronchial epithelial cells that have not been previously amenable to the mechanistic studies. The results of this work are expected to advance molecular understanding of Cr(VI) injury in the major target cells and to identify damage processing proteins that enhance toxicity of Cr-DNA modifications.
DESCRIPTION (provided by applicant):
Children born small for gestational age (SGA) have a significantly elevated risk of cardiovascular and metabolic diseases in adulthood; however, data is limited on how SGA may impact gonadal development and reproductive health. Epidemiological studies and registry surveys demonstrate that altered intrauterine growth increases the risks of congenital hypospadias, cryptorchidism and testicular cancer approximately 2- to 3-fold. Evidence for these outcomes points towards alterations in the normal functions of Sertoli and Leydig cells. Both animal and human studies suggest that impaired peri-pubertal growth can affect testis size and function into adulthood. A study by Main et al., examined testis growth from birth to 3 months of age in healthy Finnish and Danish newborns and found a significant correlation between weight for gestational age and testis size. Therefore, elucidating signaling networks which modulate peri-pubertal testis growth and identifying environmental toxicants which impinge upon these pathways will significantly impact environmental health. The Akt gene family effects testis growth. Akt1 -deficient mice are born small for gestational age and have significantly smaller testis throughout their lifetime. Preliminary data indicate that the Akt1 signaling pathway plays a significant role in maintaining peri-pubertal testicular homeostasis. A striking sensitivity is observed in vivo for germ cell apoptosis in testis of Akt1-deficient mice exposed to MEHP, a peri-pubertal Sertoli cell toxicant, and a reduction in testis and reproductive potential in mice exposed to 6-N-propylthiouracil (PTU), a thyroid toxicant which targets Sertoli cell proliferation and differentiation. Based on these findings, it is hypothesized that the Akt gene family plays a critical role in peri- pubertal testis development and that toxicants which target the Sertoli cell at this developmental window provide a crucial link between the environment and the etiology of male reproductive disease. The hypothesis will be tested through the following Specific Aims: 1.) Identify the mechanisms by which Akt1 suppresses Sertoli cell mediated germ cell apoptosis following MEHP exposure. 2.) Identify the mechanisms by which Akt1 promotes testis growth and development following PTU exposure, and 3.) Identify relevant Sertoli cell toxicant-induced stress response networks. Relevance: This research will define critical signaling networks targeted by peri-pubertal reproductive toxicants and delineate how they impact male reproductive health.
DESCRIPTION (provided by applicant)
Hepatic biliary excretion is an essential process that exists to aid the in the elimination of foreign chemicals, and protects the body from accumulating chemicals and toxicants. Understanding the underlying processes by which specific transporters that aid in biliary excretion are regulated is integral for improving human health, predicting chemical exposure, and preventing disease associated with chemical exposure. Nutrition (i.e. dietary intake, fasting, and caloric restriction [CR]) is an important factor in the susceptibility/progression of a variety of diseases associated, especially those associated with aging and environmental exposure. Trans- resveratrol (RES) is an antioxidant in red wine with anti-aging effects that mimic CR, and is an agonist for the deacetylase Sirt1. Understanding how RES, fasting, and CR regulate the expression and function of liver transporters involved in hepatic excretion (i.e. Multidrug Resistance-Associated Proteins [MRPs]) is important for understanding mechanisms by which nutrition is beneficial against chemical exposure and disease. Preliminary data demonstrates that RES increases the mRNA and protein expression of Mrp1-4, 6 in human hepatocytes and mouse liver along with induction of genes regulated by the transcription factor Nuclear Factor- E2-Related Factor 2 (NRF2), suggesting that RES activates human and mouse NRF2. Additionally, liver Mrp1, 2, and 3 expression, along with Ho-1 expression, is increased during fasting in which liver cAMP is increased and Protein Kinase A (PKA) is activated. Furthermore, constitutive activation of NRF2 in livers of KEAP1-null mice results in increased Mrp1-5 expression. The hypothesis of this proposal is that RES, fasting, and CR induce expression of MRPs through Sirt1- and PKA- upstream regulation of NRF2-mediated transcription. Specific aims will determine whether 1) RES treatment induces MRP expression in human hepatocytes and mouse liver through NRF2, 2) fasting and CR induce MRP expression via upstream activation of PKA and downstream activation of Nrf2, 3) RES, fasting, and CR induce MRP via Sirt1, and 4) RES, fasting, and CR affect bisphenol A and polybrominated diphenyl ethers (PBDE) disposition in mice. Together, these studies will define mechanisms by which nutritional status alters expression of human and mouse MRPS, as well as demonstrate whether nutritional status enhances biliary excretion of environmental chemicals. Moreover, they will also provide novel insights into mechanisms that regulate NRF2-induction of human MRP genes.
Project Narrative Nutritional status is an important factor for the development of many age-related diseases. Some environmental chemicals are thought to exacerbate or contribute to the development/progression of age- related diseases. The purpose of this project is to determine whether nutrition affects mechanisms involved in the liver's ability to uptake and clear environmental chemicals from the body.
DESCRIPTION (provided by applicant): Carcinogenic activity of hexavalent chromium (Cr) compounds is firmly established by experimental and epidemiological studies. Human exposure to Cr(VI) is found in several dozen occupations and detected in populations residing in the vicinity of Cr-emitting industrial sources and Cr disposal sites. Cr(Vl) is a major air pollutant and a Superfund contaminant. The major form of DNA damage in Cr(VI)-exposed cells is abundant Cr-DNA adducts generated in the reactions of stable Cr(III) form with DNA phosphates. We have found that several Cr-DNA adducts were mutagenic during replication in human cells. Ternary DNA adducts containing bulky ligands, such as glutathione or ascorbate, induced the strongest mutagenic responses. We also determined that Cr(III)-dependent reactions were responsible for the formation of mutagenic DNA damage during reductive activation of Cr(VI) by its major biological reducers, cysteine and ascorbate. Additional data have shown that biological consequences of the formation of Cr(III)-DNA adducts are strongly influenced by the status of DNA mismatch repair system. We propose to elucidate the mechanisms of mismatch repair-dependent induction of stress signaling and formation of genetic alterations in Cr(VI)- exposed cells. Experiments will be performed to identify specific Cr-DNA adducts that are recognized by DNA mismatch repair and activate genotoxic responses. The results of this work should provide a greater understanding of molecular basis of Cr(VI) carcinogenesis, the importance of individual Cr-DNA adducts and uncover new functions of mismatch repair in recognition of DNA backbone modifications. Identification of the most potent genotoxic Cr-DNA adducts and critical pathways controlling cellular responses to Cr(VI) can be used in the development of useful biomarkers of exposure and individual susceptibility to adverse health effects.
Crisp Terms/Key Words: p53 gene /protein, cysteine endopeptidase, gene targeting, transfection /expression vector, apoptosis, human genetic material tag, DNA damage, ascorbate, tissue /cell culture, cysteine, autoradiography, posttranslational modification, cell population study, glutathione, nucleic acid sequence, DNA repair, carcinogen testing, chemical carcinogen, chemical carcinogenesis, neoplasm /cancer genetics, chemical related neoplasm /cancer, chromium, mutagen testing, mutagen, gene induction /repression, histidine, adduct
DESCRIPTION (provided by applicant)
This Superfund Basic Research and Training Program-REUSE IN Rl: A STATE-BASED APPROACH TO COMPLEX EXPOSURES-embodies three inter-related thematic components: 1) land reuse in RI, 2) a state-based approach, and 3) complex exposures. RI is small, densely populated, and burdened by a long history of industrial activity. In this setting, there are relatively few barriers to academics, government leaders, and community members working together in an effective fashion to develop a unique state-oriented, interdisciplinary approach to land rehabilitation and reuse. This cooperative academic-government-community effort will address basic and translational research issues, management decisions, and communication barriers associated with the complex mixtures and co-exposures inherent to hazardous waste sites.
The research effort addresses theoretical and practical aspects of disease mechanisms and potential biomarkers associated with co-exposures (4 biomedical projects) and the identification, characterization, separation, and remediation of complex mixtures (3 engineering projects). These projects are supported by an Analytical Core, a Molecular Pathology Core, and a Training Core. The Research Translation Core, in cooperation with a Community Outreach Core, will facilitate the flow of knowledge and information among the participating academics, government leaders, and community members in a true university-state-community partnership. The Administrative Core provides the infrastructure to promote communication, critical self-evaluation, and resource management.
This program provides RIers with a responsive center of technical excellence that takes a research-oriented approach to resolving the complex scientific, engineering, and societal issues that arise when considering the reuse of hazardous waste sites, by focusing on the following specific objectives: 1) identify and resolve key scientific and technological issues related to chemical and physical interactions of complex mixtures at reuse sites, 2) understand basic mechanisms of toxicant-induced disease involving co-exposures, 3) effectively communicate the potential health hazards and guide the development of plans for the appropriate remediation and reuse of contaminated sites, and 4) provide expertise about complex mixtures and the health consequences of co-exposures.
DESCRIPTION (provided by applicant): Asbestos fibers persist in the lungs and cause chronic inflammation, pulmonary and pleural fibrosis, lung cancer, and malignant mesothelioma after latent periods of 20-40 years. Recent experimental evidence based on animal models using genetically engineered mice have provided new insight about the mechanistic links between chronic inflammation, fibrosis, and cancer. Recruitment and activation of inflammatory cells in response to biopersistent fibers is accompanied by release of reactive oxygen species leading to oxidant stress, DNA damage, and mutations. Inflammatory cells can release cytokines and growth factors that stimulate stromal remodeling and angiogenesis. It is hypothesized that reciprocal activation of tumor and stromal cells results in local release of matrix metalloproteinases that facilitate growth and invasion of diffuse malignant mesothelioma. In vitro, ex vivo, and in vivo assays using well characterized, transplantable murine mesothelial cell lines will be used to test this hypothesis. The specific aims of the proposed research are: 1) To determine whether induction of matrix metalloproteinases in murine peritoneal macrophages is correlated with exposure to biopersistent, carcinogenic fibers; 2) To assess the contribution of macrophages to growth and invasion of neoplastic mesothelial cells in vivo; 3) To determine whether asbestos-activated macrophages stimulate invasion of preneoplastic and neoplastic mesothelial cells; 4) To determine whether overexpression of MMP9 leads to autonomous invasion of neoplastic mesothelial cells; and 5) To assess the contribution of stromal macrophages to growth and invasion of human neoplastic mesothelial cells. Newly developed technologies including laser capture microdissection and quantitative analysis of gene expression provide powerful tools for this experimental approach. Pharmacologic modulation of persistent inflammation triggered by biopersistent, carcinogenic fibers may provide a new strategy to prevent progression of malignant mesothelioma in exposed populations.
DESCRIPTION (provided by applicant)
Uncontrolled cell proliferation is the hallmark of cancer. Exposure to certain chemicals in the environment disrupts the regulation of cell proliferation, ultimately leading to carcinogenesis. The aryl hydrocarbon receptor (AhR) binds to numerous synthetic and natural compounds including environmental carcinogens such as some polyhalogenated aromatic hydrocarbons (e.g., dioxins, polychlorinated biphenyls) and polycyclic aromatic hydrocarbons (e.g., dimethylbenzanthracene). The AhR signaling pathway has been implicated in regulation and dysregulation of the cell cycle; however the molecular mechanisms of this regulatory role are unclear. Most of the previously described interactions have been established in asynchronously growing cell cultures. The overall hypothesis of the proposed research is that AhR is a cell cycle regulator and the role it plays, either as a promoter of cell cycle progression or an inducer of cell cycle arrest, depends on its ability to differentially associate with multi-protein complexes comprised of cell cycle regulators and chromatin modifiers. This research proposes to investigate the molecular mechanisms of chemically-induced carcinogenesis initiated through activation of the aryl hydrocarbon receptor signaling pathway in mammalian cell culture models amenable to synchronization by 1) determining protein-protein interactions with chromatin modifiers (histone deacetylases and DNA methyltransferases) and cell cycle regulators (E2F transcription factors, retinoblastoma [RB] tumor suppressors) at specific stages of the cell cycle, 2) assessing the targeting of cell cycle gene promoters by AhR-containing transcriptional complexes by chromatin immunoprecipitation (ChIP) experiments and genomic approaches including ChlP-on-chip and ChlP-cloning, and 3) determining how the regulatory role of AhR is disrupted by carcinogenic AhR ligands. The results from this research will provide a better understanding of chemically-induced carcinogenesis and gain insight into the molecular mechanisms for the varied responses in the cell cycle observed following exposure to environmental toxicants. Furthermore, the results will provide the basic research for developing therapeutic interventions to chemical-induced tumors and may predict cell cycle stages susceptible to cancer.
DESCRIPTION (provided by applicant)
Gallstone disease affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Gallstones can cause extrahepatic cholestasis by occluding the common bile duct. In bile, bile acids and phospholipids are important for the solubilization of cholesterol. When the composition of bile changes such that the ratio of bile acids to cholesterol decreases (either decreased bile acid synthesis and/or increased cholesterol secretion into bile), the probability for formation of cholesterol gallstones increases. The broad objective of this proposal is to understand how the transcription factor Nuclear Factor-E2-related factor 2 (Nrf2) regulates cholesterol and bile acid metabolism and disposition during cholestasis and during exposure to a high cholesterol diet. Preliminary studies show that liver transporter expression is different in livers from wild-type (WT) mice and Nrf2-null mice during cholestasis. Thus, Specific Aim 1 will expand upon these initial findings and determine whether drug disposition differs between WT and Nrf2-null mice during cholestasis. Importantly, preliminary studies also demonstrated that bile acid levels are decreased in liver and serum from Nrf2-null mice as compared to WT mice, suggesting that Nrf2 is important for bile acid synthesis. Therefore, Specific Aim 2 will determine the mechanism by which Nrf2 regulates bile acid levels in liver. Preliminary data also indicated that Nrf2-null mice exhibit increased formation of cholesterol gallstones when exposed to a high cholesterol diet, and studies in Specific Aim 3 will determine the mechanism by which Nrf2-null mice are more susceptible to gallstone formation. Studies in aim 3 will examine biliary cholesterol, bile acid, and phospholipid secretion as well as examine differences in heptic expression of genes for cholesterol and bile acid synthesis, metabolism, and disposition. Together, the proposed studies will provide novel information regarding liver regulation of cholesterol and bile acids and provide valuable insight into the pathogenesis of gallstone formation.
DESCRIPTION (provided by applicant)
The objective of this predoctoral and postdoctoral training program is to educate a new generation of environmental pathologists to use the tools of cell biology, molecular biology, and biochemistry to study basic mechanisms of disease related to environmental exposures. The central focus is an independent laboratory research project to explore the pathogenesis of altered reproductive function, adverse developmental and pregnancy outcomes, neurodegenerative disease, or cancer resulting from exposure to industrial wastes and environmental contaminants including metals, plasticizers, pesticide, particulates and fibers. Predoctoral trainees will be recruited with majors in biology, chemistry, toxicology, or environmental sciences and a commitment to basic research on mechanism of disease and environmental health. Postdoctoral trainees may hold a doctoral degree in a basic science discipline, pathology, or toxicology. All predoctoral trainees are required to learn the basic mechanisms and morphologic manifestations of human disease. Training is also required to learn the basic mechanisms and morphologic manifestations of human disease. Training is also provided in molecular pathology, imaging, and environmental toxicology, signal transduction, carcinogenesis, and molecular genetics. All trainees will be instructed in the responsible conduct of research and will have the opportunity to develop their communication and teaching skills at the Sheridan Center for Teaching and Learning at Brown University. Didactic courses are supplemented by weekly research seminars, student journal clubs, career development workshops, and an annual Environmental Pathology Symposium, Strong emphasis is placed on communication skills, grantsmanship, interdisciplinary approaches, and implications of basic research for recognition and prevention of human disease. Opportunities are provided for clinical and translational research collaborations at Rhode Island Hospital and Women & Infants' Hospital, as well as field work and community outreach at existing industrial waste sites and Brownfields in Rhode Island. The eight faculty have active, well-funded research programs ($4.4 million in annual direct costs) and access to modern research facilities equipped for quantitative imaging, laser capture microdissection, genomics and proteomics, flow cytometry, transgenic animals, and access to human tissue and specimen banks. These trainees will be prepared to apply their basic research expertise to the definition, analysis, and solution of complex environmental health problems working together with experts in epidemiology, toxicology, public health, and government and regulatory agencies.
BACKGROUND
This Training in Environmental Pathology program is in its 14th year of support and is centered in the department of Pathology and Laboratory Medicine in the Division of Biology and Medicine at Brown University. The program enlists eight faculty, five of which are physicians, as mentors that have environmental related research in the areas of pulmonary, hepatic, reproductive and neurological health. The research focuses on mechanistic, translational and public health outcomes from environmental agents and common cofactors. Dr. Agnes Kane MD/PhD has acted as Director of the program since its inception and the Co-Director is Dr. Kim Boekelheide MD/PhD. The application requests funding for five predoctoral and two postdoctoral positions.
Recruitment of a new Dean in 2005 with a strong mandate to improve graduate education in the Division of Biology and Medicine was considered an advantageous asset to the Environmental Pathology Training Program. In 2006 the Training Program recruited its largest applicant pool. It was noteworthy that the program has over $4 million in direct cost funding. A major change in the predoctoral curriculum was a reduction in the number of required courses and seminars and transfer of the first research rotation to the first semester. This change was considered to facilitate the trainee's selection of a thesis research mentor at the end of the second semester and to facilitate the trainee's progression to completion of the preliminary examination at the end of the second year. The program has multiple interactive activities with trainees to address the responsible conduct of research. In response to feedback received via internal and external reviews the number of invited speakers representing diverse career pathways has been increased.
This application seeks continuing support (years 16-20) for training in the environmental pathology track within the Pathobiology Graduate Program at Brown University. This program is part of the Division of Biology and Medicine and Center for Environmental Studies. Eight preceptors are named in the renewal application, down from ten named in 2001.
DESCRIPTION (provided by applicant): Rapid upregulation of the arginine-sensitive amino acid transporter TA1/LAT1/CD98 light chain in response to carbon tetrachloride-induced injury has been demonstrated in previous studies. LAT1 is suggested to have an adaptive role in response to liver injury, yet the underlying downstream mechanisms remain to be elucidated. These studies will focus on the changes in expression of LAT1 and its downstream markers in response to (and comparison with) carbon tetrachloride exposure and amino acid availability. Genes that are found to be differentially expressed may be biomarkers for predicting toxicity. Microarray gene analysis coupled with bioinformatics will be used to identify gene sets of interest. Selected genes will be verified for differential expression using Western blotting, Northern blotting, proteomics, immunoprecipitation and PCR techniques. This proposal aims to test the hypothesis that alterations in gene expression observed at early time points after toxicant exposure will include many genes that respond to other environmental exposures and stresses including nutrient availability and viral infection. It is predicted that genes involved in oxidant and metabolic stress responses, such as LAT1, will be central in adaptation following liver injury.
DESCRIPTION (provided by applicant)
Adverse human health effects due to occupational and environmental exposure to nanomaterials are a major concern and a potential threat to their successful commercialization and biomedical applications. Realization of their commercial potential will require a better understanding of the interactions of nanomaterials with biological systems and the development of new strategies to manage human health risk. Manufactured carbon nanomaterials are highly variable with respect to chemical and physical properties, state of aggregation, and purity. Toxicological screening is urgently needed to identify potentially hazardous nanomaterials; however, their wide variability and unique properties complicate interpretation of traditional in vitro and in vivo toxicity assays. An interdisciplinary research team at Brown University including a materials scientist, a toxicologic pathologist, and a molecular biologist has developed a panel of novel nanomaterials and innovative approaches for nanotoxicology assays. This panel of model nanomaterials will be expanded to include selected commercial materials subjected to rigorous characterization of lexicologically relevant materials properties. Novel synthesis and characterization methods will be used to carry out systematic studies (Specific Aims 1 and 2) that reveal the chemical (surface state, metals bioavailability, biopersistence), structural (size, shape, elasticity), and superstructural (aggregate size and shape) basis of carbon nanomaterial toxicity. This team will develop and validate a unique platform for cellular assays in 3- dimensional culture using formation of granulomas, persistent macrophage activation, and fibrosis as pathologic endpoints (Specific Aim 3). This platform will incorporate post-exposure characterization of nanomaterials in parallel with an acellular assay to assess biopersistence and aggregation state in simulated intracellular environments (Specific Aim 4). A cytokine expression profile will be developed to predict toxicity of carbon nanomaterials relative to standard reference materials (Specific Aim 5). It is anticipated that this validated toxicologic screening assay will provide an alternative to chronic rodent inhalation assays at lower cost and reduced burden of animal testing. Identification of specific chemical and physical properties of nanomaterials responsible for cellular toxicity will enable development of manufacturing methods and post processing steps to eliminate intrinsic toxicity.
DESCRIPTION (provided by applicant): Carboxylesterases represent a large class of hydrolytic enzymes that play important roles in the metabolism of endogenous lipids, pharmacological determination of therapeutic agents and detoxication of organophosphorus insecticides. The focus of the current grant period has been on molecular cloning, enzyme kinetics and xenobiotic regulation. Enzymatic characterization and molecular modeling have revealed that carboxylesterases contain several functional subsites (structures) that likely play determinant roles in substrate recognition and inhibitor reactivity. Carboxylesterases, with the same functional subsites exhibit the same substrate preference and a similar sensitivity to serine enzyme inhibitors. Studies on xenobiotic regulation have demonstrated that dexamethasone suppresses the expression of rat hydrolase A, B/C and S, whereas the expression of human HCE-1 and HCE-2 is induced by this drug. Suppression requires only nanomolar whereas induction requires micromolar levels. The proposed studies are designed to test the hypotheses that non-conserved residues assumed to form functional subsites among carboxylesterases contribute significantly to the observed differences on the substrate preference and that the dexamethasone-directed suppression of rat carboxylesterases is mediated by the glucocorticoid receptor whereas the induction of human carboxylesterases is mediated by the pregnane X receptor. The specific aims of the proposed studies are: (1) to characterize functional subsites determining substrate and inhibitor selectivity; and (2) to elucidate molecular basis for species-dependent regulation by dexamethasone. Site-direct mutagenesis will be performed to replace a single residue or an entire putative subsite, and the mutants will be tested for the altered hydrolytic activity toward structurally dissimilar substrates. Studies on cell proliferation and toxicity will be performed to determine whether changes in catalytic properties translate into actual perturbations in biological functions. In order to specify the receptor involved in the species-dependent regulation by dexamethasone, antiglucocorticoids and dominant regulators will be used to selectively block or alter either pathway and the role of each receptor will be established in regulating carboxylesterase expression. Establishment of the importance of the subsites for substrate recognition will provide information to elucidate the catalytic action of carboxylesterases and to ascertain isoform-based pharmacological and toxicological relevance. Specification of a receptor involved in dexamethasone-mediated regulation will provide molecular mechanisms to predict potential drug-drug interactions as a result of altered expression of carboxylesterases.
Crisp Terms/Key Words: dexamethasone, laboratory rat, carboxylic ester hydrolase, catalyst, polymerase chain reaction, enzyme inhibitor, enzyme mechanism, site directed mutagenesis, reporter gene, liver cell, chemical model, high performance liquid chromatography, corticosteroid receptor, toxicology, cytotoxicity, toxin metabolism, SDS polyacrylamide gel electrophoresis, gel mobility shift assay, cell proliferation
DESCRIPTION (provided by applicant)
This proposal is support for a new Gordon Research Conference, the 2008 Oceans and Human Health Gordon Conference (GRC) and its preceding Graduate Research Seminar: Oceans and Human Health (GRS). These meetings will take place June 28-29, 2008 (GRS) and June 29-July 4, 2008 (GRC). The subject of Oceans and Human Health concerns science at the intersection of medical, genomic and oceanographic disciplines, and the implications for and effects on human health and wellbeing. These effects often reflect complex processes whose elucidation requires an integration of information and knowledge from the medical, marine, and social sciences. Sources and impacts including human health effects and economic consequences of marine toxins and pathogens continue to be of great concern in this developing area of Oceans and Human Health. Of growing concern are human health effects from exposure to substances that occur widely in marine ecosystems [including synthetic organic chemicals, polycyclic aromatic hydrocarbons (PAHs), metals (both introduced and anthropogenic)]. In addition, increasing consensus exists concerning the human health impacts of global warming and extreme events associated with the coasts and oceans. On the positive side, marine organisms, including in particular marine microbes, are a largely unexplored source of pharmaceuticals and other pharmacologically active products for the treatment of human diseases and dietary deficiencies, and fish and shellfish are important sources of high quality protein and omega-3 polyunsaturated fatty acids in the human diet.
The purpose and scope of the Gordon Research Conference (and its associated Graduate Research Seminar) on Oceans and Human Health are to provide a multidisciplinary platform for discussing the current state of knowledge of the rapidly evolving, highly interdisciplinary field of Oceans and Human Health, to identify and debate unresolved questions, and to discuss new research directions. The Conference and the Graduate Research Seminar will bring together experts and students with diverse backgrounds including algal and microbial biology, physical and biological oceanography, epidemiology and public health, genomics and proteomics, toxicology, pharmacology, and economics. The topics the investigators propose to cover include aspects of these disciplines involving broad and focused areas. Through formal presentations, poster sessions and informal interactions between scientists and students, the Conference will help define and move the field forward. An important motivation for the proposed Gordon Research Conference and its associated Graduate Research Seminar is that as a new scientific discipline, Oceans and Human Health does not have a forum to facilitate interactions and dialogue among the scientists and students involved in research relevant to oceans and human health. The significance of the field is reflected by the support of Centers for Oceans and Human Health by the NIEHS and the National Science Foundation.
DESCRIPTION (provided by applicant)
The sixth Gordon Research Conference (GRC) on Environmental Endocrine Disruptors (EED) will be held June 8-13, 2008, in Waterville Valley Resort, New Hampshire. It was designed to achieve two goals. First, this conference will mark the 10th anniversary of the first GRC on EED, an event that has markedly influenced the growth of this field of research. One example: between 1998 and 2006 the annual number of Medline citations for the key words "endocrine disruption/disruptors" has grown by twenty-fold. To maintain this pace of growth, the 2008 conference seeks to highlight the important advances over that period and to help shape the next decade of research. Second, the conference aims to highlight the most recent science through discussions of new candidate EEDs, newly discovered and proposed mechanisms of action, new endpoints under investigation as targets of EEDs, and new methods for evaluating health and ecological risks attributable to EED exposure. The list of speakers includes leading scientists from the US, Japan and Europe, as well as young scientists who have recently reported exciting findings. Endocrine disruptors are now thought to influence the development of not only male and female reproductive systems, but also to be involved in the development and adult functions of numerous organ systems (including metabolic, immune and thyroid, bone, and brain), as well as playing a role in the onset and progression of several types of cancers. Governments of the United States, Japan and the European Union have enacted laws regulating endocrine disrupters (most recently REACH) and in the U.S., amendments were passed to the Safe Drinking Water Act and the Food Quality Protection Act mandating the testing of chemicals found in water and food for endocrine-disrupting activity. Public interest in endocrine disruptors has grown at the same pace as the science. The GRC represents a unique venue for promoting research and the exchange of information and viewpoints in this critical area of environmental health. The proposed conference adheres to the guiding principle of the GRC that the presentations are to be of new, unpublished work and that the discussions are to be open and unhampered. There is a tradition of freely sharing ideas in an "off the record" atmosphere, without the constraining publication of conference proceedings. This underlying philosophy is critical because the proposed topics are positioned at the cutting edge of current science. The proposed conference embodies a subject area with interdisciplinary and multidisciplinary dimensions, and will convene a diverse group of international scientists whose studies and interests range from effects in and exposures of human populations, to ecological effects and exposures in wildlife. These interests extend to basic research in animal models and novel in vitro systems. In addition to the NIEHS, this conference is of potential interest to the National Institute on Aging (NIA) and the National Institute of Child Health and Human Development (NICHD), both of which have agreed to be named as secondary on this application.
DESCRIPTION (provided by applicant)
The Mechanisms of Toxicity Gordon Research Conference has developed a rich tradition of excellence in the dissemination and promotion of research in the toxicological sciences. The fiftieth anniversary of the Mechanisms of Toxicity conference and the seventy-fifth year of the Gordon Research Conferences will be celebrated in 2006. This conference has been held biannually since 1956 and has become the premier scientific meeting focusing on the molecular mechanisms of chemical injury and the pathogenesis of environmental human disease. The topics to be covered in 2006 include i) Glycogen Synthetase Kinase 3 Beta Phosphorylation: Risks and Benefits; ii) Chemical Mechanisms of Xenobiotic Bioactivation and Toxicity; iii) Ubiquitin Proteosome System; iv) Transporters: Proteins of Emerging Importance in Xenobiotic Disposition and Toxicology; v) Mechanisms of Nucleocytoplasmic Trafficking; vi) Mitochondrial Mediated Metabolic Diseases; vii) Fetal Basis of Adult Disease; and vii) Cell-cell Interactions that Mediate Organ System Toxicity. The program includes internationally recognized leaders and talented new investigators from the United States and abroad. Time has been allotted for junior investigators to present their work in late breaking research and poster sessions. Chairs and co-Chairs will stimulate discussion and scientific dialogue to maximize participation and increase interactions among senior and junior investigators, postdoctoral fellows and graduate students. The 2006 Mechanism of Toxicity Gordon Research Conference has been organized to include the latest information in the field of toxicology and will continue its long tradition as the leading small conference in toxicology.
DESCRIPTION (provided by applicant)
This proposal requests partial support for the 4th Gordon Research Conference on Environmental Bioinorganic Chemistry (EBIC 2008) to be held in Waterville Valley, NH, 15-20 June 2008. The broad and long term goal for this conference is to understand the roles in biotic processes of elements historically called "inorganic" at scales from the molecular to the global. Technical challenges will allow the investigators to overlook that living systems consist of more than carbon, hydrogen, nitrogen, phosphorus, and oxygen, but they now know that the biosphere depends on, or can be vulnerable to, a much larger portion of the Periodic Table. Moreover, while human use of some inorganic elements is ancient, modern industry and agriculture have led to unprecedented exposures of humans and their environment to toxic elements and radionuclides with costly consequences for public health. The investigators aim specifically to convene for 5 days in a lovely natural setting with 36 speakers/ discussion leaders who study bioinorganic chemistry at different scales of biological organization (molecular to ecosystem) and with diverse perspectives and tools. EBIC 2008 will open with two keynote addresses on the cellular and global dimensions of our subject. There will be seven sessions covering iron and sulfur, trace metals, mineral nutrition and homeostasis, inorganic aspects of evolution, toxicology and bioremediation, bioenergy and nanotechnology, and recent advances in bioinorganic analysis. Two pre-dinner poster sessions (2-days each) will afford all registrants the opportunity to discuss their science with each other. The conference will close with a remembrance of a seminal contributor to bioinorganic chemistry. The significance of this conference is that while other meetings focus on metallobiology at the molecular and cellular levels or include bioinorganic topics in their environmental focus, EBIC has been unique in deliberately bringing these distinct perspectives together to make connections among bioinorganic processes across spatial and temporal scales and to foster discovery of common and disparate patterns in such processes across the Periodic Table. The health relatedness of the EBIC 2008 conference is that human and animal health and both chronic disorders and defense against infectious diseases depend on adequate mineral nutrition, made possible by plant and microbial acquisition of inorganic elements directly from soil and water. In addition, modern farming, manufacturing, clinical, and military practices have substantially increased our exposure to toxic elements generating a need to understand and monitor their risks and devise strategies to protect against them. The health relatedness of the EBIC 2008 conference is that human and animal health and both chronic disorders and defense against infectious diseases depend on adequate mineral nutrition, made possible by plant and microbial acquisition of inorganic elements directly from soil and water. In addition, modern farming, manufacturing, clinical, and military practices have substantially increased our exposure to toxic elements generating a need to understand and monitor their risks and devise strategies to protect against them.
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