Word (http://tools.niehs.nih.gov/portfolio/sc/list_doc.cfm?ext=.doc)
|
Excel (http://tools.niehs.nih.gov/portfolio/sc/list_xls.cfm?ext=.xls)
|
PDF (http://tools.niehs.nih.gov/portfolio/sc/list_doc.cfm?pdf=1&ext=.pdf)
Record Count: 7
To sort columns alphabetically or numerically, click on the column
header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant):
The goal of this project is to elucidate redox-responsive developmental pathways and gene regulatory networks that mediate susceptibility to environmental redox stressors. Redox chemistry is at the core of biology, providing the energy that fuels life but also producing toxic byproducts in the form of reactive oxygen species (ROS). ROS production can lead to oxidative stress, a hallmark of many human diseases (such as diabetes) and environmentally-induced pathologies (such as those associated with alcohol abuse). Biological signaling systems are therefore often responsive to redox chemistry. While many environmental redox stressors are also known to cause developmental malformations in humans, particularly in the developing nervous system, the redox-sensitive regulatory networks that mediate this susceptibility are largely unknown. The sea urchin embryo provides a useful comparative model for addressing this problem, as its genome has been sequenced and annotated, and because of the fact that it is a deuterostome and hence developmentally more similar to humans than other invertebrate model organisms. A number of findings indicate that ectodermal cell fate along the oral-aboral axis of the sea urchin embryo is specified via a redox-sensitive regulatory network, and can be specifically perturbed (radialized) by redox stressors such as metal ions and hypoxia. Ectodermal cell fate specification is mediated by Nodal signaling, which in turn is dependent on p38 mitogen activated protein kinase (MARK). The specific aims of this project are to (1) test the hypothesis that p38 mitogen activated protein kinase (MARK) activity is regulated by redox signaling in the developing ectoderm; (2) identify redox-responsive cis-elements and transcription factors that regulate Nodal activity; and (3) identify pathways through which redox stressors perturb ectodermal patterning and affect human development and disease. To achieve these aims, the project will make use of highly specific molecular reagents including mitochondrially-targeted enzymatic anti-oxidants, morpholino-antisense mediated knockdown, and cis-regulatory analysis of the Nodal gene. In addition, a microarray approach will be used to identify the redox-sensitive transcriptome. Finally, the Comparative Toxicogenomics Database (CTD) at MDIBL will be used to determine the relevance of the pathways discovered in sea urchins to human health, and to generate hypotheses that might explain specific human diseases.
This grant proposal is a request for the renewal of funding for the Center for Membrane Toxicity Studies, an NIEHS Marine and Freshwater Biomedical Sciences Center (MFBS), located at the Mt. Desert Island Biological Laboratory (MDIBL) in Salisbury Cove, Maine. The goal of this Center since its inception in 1985 has been to involve a group of internationally recognized scientists, who are experts in mechanisms of epithelial transport, to study the biological effects of environmental pollutants on cell and membrane transport functions. The focus of these efforts has been to elucidate the mechanisms of toxicity and pathways of excretion of environmental toxicants at the cellular and molecular level using novel aquatic models developed at this laboratory. This Center grant facilitates this effort by providing: a) administrative and research facility support, b) pilot-feasibility grants to attract new investigators to work on Center goals,
and c) community outreach and educational programs that include student education programs (minority and local high school students), and shared activities with environmental groups in local high schools. In addition to the Administrative Core, the Center is composed of 5 Facility Cores: an Animal Core, Instrumentation Core, Cell Isolation, Culture and Organ Perfusion Core, an Imaging Core, and a newly formed Bioinformatics Core. The Research Base of the Center includes a core group of 21 investigators (Bain, Baldwin, Ballatori, Barnes, Boyer, Callard, Dranoff, Forbush, Forrest, Fricker, Henson, Kinne, Kullman, Mattingly, Miller, Renfro,
Riordan, Sate, Stanton, Villalobos and Xiao) who focus on two common research themes: 1) signal transduction and ion transport, and 2) xenobiotic transport and excretion. Investigators in the Pilot Feasibility Program also contribute to these research themes. While the research activities of this Center were traditionally seasonal, the Center's research base is now increasingly a year-round scientific activity both at the MDIBL and at the investigators' home institutions.
DESCRIPTION (provided by applicant): Millions of people throughout the world are suffering from chronic arsenic poisoning due to the consumption of contaminated drinking water. Although it is well known that adults experience neurotoxicity when they are acutely exposed to high doses, the developmental neurotoxicity of arsenic is poorly understood. This data gap is alarming because the toxic effects that result from exposure during critical periods of brain development are often permanent and are expressed later in life as behavioral impairments. The proposed research will fill this void by examining a series of reflexive, motor, attention, and learning behaviors following developmental exposure to trivalent arsenic (the most toxic form) in drinking water. These behavioral endpoints will be examined in the C57BL6 inbred mouse strain. Both male and female mice will be examined to identify sex-specific responses. The behavioral tests were carefully selected because each is dependent on the integrity of dopamine or norepinephrine systems in the frontal cortex, hippocampus, basal ganglia, or cerebellum. Previous research has shown that arsenic can increase or decrease catecholamine levels in the brain depending on the dose. It is hypothesized that arsenic exposure during development produces long-term effects on forebrain catecholamine systems. A second objective of the proposed research is to use immunohistochemistry and confocal microscopy to examine the effects of arsenic on the distribution and density of catecholamine neurons in the adult brain. A reduction of the number of neurons in the adult brain may be due to early changes. In vitro studies have shown that arsenic increases neuronal apoptosis. Therefore, it is hypothesized that arsenic exposure during development increases apoptosis in forebrain catecholamine systems. A third objective for this research is to use the TUNEL staining technique to label apoptotic neurons in the neonatal frontal cortex, hippocampus, basal ganglia, or cerebellum. Millions of people worldwide consume arsenic-contaminated drinking water. Some of the affected individuals are pregnant women and the developing fetus is particularly sensitive to arsenic toxicity. The proposed research is designed to determine how inorganic arsenic impairs cognitive function following gestational exposure.
DESCRIPTION (provided by applicant):Numerous findings have raised the level of national concern that chemicals found in the environment may have adverse effects on humans and wildlife. The Environmental Protection Agency's (EPA's) recent reassessment of dioxin toxicity concluded that body burdens of many individuals might exceed threshold levels that trigger developmental delays and hormonal changes. Additionally, this evaluation indicates that the dioxin-associated cancer risk is 10-fold higher than previous estimates. Environmental exposures have been implicated in contributing to gonadal tumors in eastern Maine softshell clams (M. arenaria); tumor prevalence as high as 40% has been observed in some feral populations. Tumor incidence has been correlated with the use of the herbicides 2,4 dichlorophenoxyacetic acid (2,4-D) and dioxin-contaminated 2,4,5-trichiorophenoxyactic acid (2,4,5-T). Epidemiological studies of women in the same geographical area document mortality rates from reproductive system cancers that are higher than the national average. These observations suggest that environmental exposures may contribute to the etiology of these cancers and to other reproductive effects. Understanding the molecular mechanisms by which tumors develop in the clam model may provide important information on the effect of chronic low-level environmental exposures and allow us to better extrapolate possible health risks to humans. Laboratory exposures established that bivalves accumulate dioxin, with the gonad serving as a reservoir. Dioxin exposure induced differential gene expression and both dioxin and herbicides had significant, negative impact on gametogenesis. The investigators have cloned a clam homologue to the vertebrate aryl hydrocarbon/dioxin receptor (AHR) that demonstrates structural similarity to human AHR. Continuation of these studies will focus on: 1) clam AHR characterization (e.g., ligand identification, protein-protein interactions, and biological activity); 2) further investigation of environmental toxicant impact on cell-cycle regulation pathways (e.g., stimulation of E3-mediated degradation of p53); and 3) short- and long-term laboratory exposures to herbicides and dioxin to evaluate effects on reproductive fitness.
DESCRIPTION (provided by applicant): The goal of this proposal is to establish an authoritative public database, the Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org), that promotes understanding about the effects of environmental chemicals on human health. The etiology of most chronic diseases involves interactions between environmental and genetic factors. Although more than 85,000 chemicals are used in commerce today, the complex molecular mechanisms underlying the actions of most of these chemicals and their effects on human health are poorly understood. In CTD we will present scientifically reviewed information on environmental chemicals, significant genes, and their interactions in vertebrates and invertebrates. The specific aims of this proposal are to: 1) curate and integrate chemical-gene interactions from published literature and high-throughput experimental data (e.g., microarrays); 2) curate cross-species toxicologically important genes and their proteins; and 3) transform the CTD prototype into a robust, production-quality database ready for increased public use and more sophisticated data search and analysis capabilities. CTD will be the first database to focus its curation on chemical-gene interactions and genes of toxicological significance in diverse species to elucidate structure-function correlations. These data will be key to building network models of chemical actions and providing important insights into differences in susceptibility to environmentally-induced toxicity and disease. Insights from CTD will also have important implications for toxicity prediction and environmental regulation. We are developing the publicly available Comparative Toxicogenomics Database (CTD) to promote understanding about the effects of environmental chemicals on human health. CTD will provide information on significant chemicals, genes, and their interactions in vertebrates and invertebrates. These data will provide important insights into the mechanisms of chemical actions and the genetic basis of differential toxicity among organisms and individuals, and will also have important implications for toxicity prediction and environmental regulation.
DESCRIPTION (provided by applicant): Zeomatrix, a small business, is proposing to research and develop a remediation technology for chlorinated volatile organic carbons (CVOCs). CVOCs are ubiquitous groundwater pollutants. Left on their own they persist in nature for over 100 years. Most are toxic to humans, and some (including trichloroethylene) have been linked to cancer. A recently completed 17 year study by the United States Geological Survey found that chlorinated VOCs are present in nearly every aquifer in the United States. It is estimated that full scale remediation of these compounds in groundwater will cost in excess of $200 billion. The product being developed is a visible light photocatalyst which will promote the rapid reduction of CVOC compounds to less toxic materials. Current commercial photocatalysts are employed as oxidative catalysts, and thus they are less efficient at remediation in the presence of dissolved organic matter, a common component of groundwater. Zeomatrix utilizes high throughput screening methods to rapidly and cost effectively develop new photocatalysts. The Phase I research will be performed using custom-designed parallel photocatalyst screening instrumentation in order to evaluate a large number of candidate materials and identify the optimal reductive photocatalyst. The research will be focused on the following specific aims: one, to synthesize an array of catalyst support geometries based on design of experiments (DoE) protocol and using an automated deposition system custom-engineered by Zeomatrix to deposit various metal/metal oxide combinations and then screen for reductive photocatalytic activity under visible light; and, two, to screen the reductive photocatalysts selected from the initial screening experiments for activity versus chosen test compounds (trichloroethylene, trichloroethane), under a range of experimental conditions (pH, ionic strength, dissolve organic content). Selection of the optimal photocatalyst will be based on rapid degradation kinetics (turn over frequency), and efficacy under adverse conditions (high ionic strength, pH extremes, and high dissolved organic content). The results of the Phase I research will be used to determine the feasibility of applying the selected photocatalyst for the remediation of CVOCs. Phase II studies would be performed to further optimize the photocatalyst, and to perform a large scale pilot study on actual polluted groundwater. The combination of rapid kinetics with the use of low cost visible light would make this an attractive remediation option to address the extensive problem of CVOC contamination.
The goal of this research is the development of a novel remediation technology for the break down of chlorinated volatile organic carbons in water. Chlorinated volatile organic carbons are found in nearly every aquifer in the US. Left on their own they persist in nature for over 100 years. Most are toxic to humans, and they accumulate in fatty tissue making them a danger to human health even at low levels. Some have been linked to cancer and over twenty are currently regulated in public water supplies by the United States Environmental Protection Agency.
DESCRIPTION (provided by applicant)
The Mount Desert Island Biological Laboratory (MDIBL) and the NIEHS Center for Membrane Toxicity Studies (CMTS) at MDIBL propose a Short-Term Educational Experience for Research (STEER) for six Maine high school students. The overall goal of the MDIBL STEER program is to match selected students with NIEHS Center investigators for a hands-on research experience in the environmental health sciences. The scientific theme is "Pathways of Chemical Action in Human Disease", which parallels the Center's mission to elucidate the mechanisms of toxicity and pathways of excretion of environmental toxicants at the cellular and molecular level. In addition to the research experience, each student will assemble a fellowship portfolio, including their laboratory notebook, and other components to document their fellowship. Students will participate in external activities to enrich the laboratory experience including journal club meetings, scientific seminars, and presentations. The Center for Research and Evaluation at the University of Maine will conduct program evaluation and analysis, as well as short-term student follow-up. MDIBL will track the educational and career paths of STEER participants beyond their completion of the STEER program. STEER administrators will work with local high school teachers who will nominate students to apply to the program, and who will help MDIBL identify students underrepresented in science by virtue of their ethnicity, race, or individuals from economically or educationally disadvantaged backgrounds. The specific aims of the MDIBL STEER program are: 1. To provide Maine high school students with multidisciplinary research experiences in the environmental health sciences with applications to human health, mentored by nationally recognized basic scientists and physician scientists and 2. To serve as a pipeline for Maine high school students to continue in undergraduate and graduate degree programs in the environmental health sciences.
|