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: 12
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): Therapeutic irradiation is known to induce DNA damage, which activates multiple signaling pathways, cell cycle checkpoints and gene transcription. Induction of a cell-cycle checkpoint is a critical mechanism by which cells respond to the damaging and cytotoxic effects of irradiation and arrest their growth. Emerging evidence suggests that histone deacetylase 1 (HDAC1) plays a critical role in the regulation of Pol-II mediated gene transcription. Protein phosphatase-1 (PP1) is a serine/threonine protein phosphatase that controls diverse cellular processes including transcription and cell cycle progression. New data from our laboratory link PP1 not only to the transcriptional regulator HDAC1 but also the key cell-cycle regulators Rb (G1 progression) and Nek2 (a key kinase regulating centrosome separation). Our data clearly establish that: (1) PP1 is activated by dephosphorylation of T320 as a result of an IR-activated, ATM-dependent signaling pathway in the absence of radiation, (2) PP1 physically associates with Rb and HDAC1 as well as with Nek2 to form two discrete complexes, (3) IR activates PP1 in both of these complexes, (4) IR activates HDAC1 and also induces dissociation of both Rb and HDAC1 from PP1, and (5) IR inhibits Nek2 through PPI.
The long-term goal of this project is to develop novel targets for chemo/radiation sensitizers by delineating the role of the multiprotein complexes consisting of PPI:RB:HDAC1 and PP1 :Nek2 in the induction of IR cell-cycle arrest and gene transcription. We hypothesize that IR causes reduction in T320 phosphorylation of PPlc, resulting in activation of PP1 and release of Rb and HDAC1 from a pre-formed complex in an ATM-dependent process as well as inhibition of Nek2 (PP1 is known to be a negative regulator of Nek2). IR-activated PP1 is critical for checkpoint activation through dephosphorylation of Rb and Nek2 and gene transcription through its regulation of HDAC1 activation. We will test this hypothesis by performing the following specific aims:
Aim 1. Identify the molecular mechanism used by PP1 to regulate the damage response.
Aim 2. Determine if IR induces the recruitment or dissociation of proteins from the multiprotein complex consisting of Rb, PP1 and HDAC1.
Aim 3. Determine the role of IR-activated PP1 in the regulation of HDAC1.
DESCRIPTION (provided by applicant): The U.S. EPA (Suppl Guidance for Conducting Health Risk Assessment of Chemical Mixtures, 2000) suggests that when toxicity data are not available for a mixture of concern, the risk assessment of the mixture can be based on data for a surrogate mixture which is considered "sufficiently similar" in terms of chemical composition and component proportions, and when available, considerations of similar biological disposition and toxicity. The objective of this research is to develop methodology to define sufficient similarity in dose-responsiveness for mixtures of many chemicals containing the same components, but whose component ratios vary. The method assumes that dose-response data on a fixed-ratio mixture are available. Statistical equivalence testing logic will be applied to define boundary ratios for mixtures with mean, dose-response relationships sufficiently similar to an observed mixture, based on a specified biologically meaningful region of insensitivity as defined by the investigator using expert judgment. Once the methodology is further developed as described herein, simulation studies will be conducted to elucidate the properties of the approach. The simulation study will be based on data from at least three dose-response curves of mixtures of chemicals including: (1) a mixture of 11 pesticides (pyrethroids) and the effect on neurotoxicity; (2) a mixture of 18 polyhalogenated aromatic hydrocarbons in a fixed ratio based on evaluation offish tissue, breast rnilk and other sources of human exposure and the effect on thyroid disruption; (3) a mixture of 5 organophosphorous pesticides in a relevant ratio based on dietary exposures and the effect on neurotoxicity. The result of this research will impact public health by adding new approaches to the risk assessment of chemical mixtures. In particular, all possible environmentally/industrially relevant chemical mixtures to which humans are exposed cannot each be evaluated for risk. The funded project will further develop/characterize a method of determining sufficient similarity in dose-responsiveness for mixtures with many components.
DESCRIPTION (provided by applicant): Although acquired cytogenetic changes have been implicated in several human conditions (especially cancer), their cause(s) are poorly understood. Do individuals have a genetic predisposition to develop genomic changes or is the frequency of abnormalities most heavily influenced by environmental factors? Does telomere shortening contribute to an increased frequency of acquired chromosomal abnormalities in humans? To answer these primary questions, we will determine (1) the frequency of acquired chromosomal changes in lymphocytes and buccal mucosa cells; and (2) chromosome-specific telomere lengths in identical (MZ) and fraternal (DZ) twins. The cytogenetic abnormalities will be identified for each of the 24 human chromosomes using a novel assay we developed which combines spectral karyotyping (SKY), fluorescence in situ hybridization (FISH), and micronuclei technologies. The chromosome-specific telomere lengths will be determined using newly developed methods that exploit FISH-based and DMA combing technology, the latter of which allows for unprecedented resolution (as small as 1-3 kb) in measures of chromosome length. These telomere and chromosome abnormality measures will be obtained for 220 same-sex twin pairs (110 MZ and 110 DZ pairs). The twins will vary in age (ranging from 6 y.o. to at least 80 y.o.) to allow us to quantify the association between aging and the acquisition of chromosomal aberrations. The extent to which individual differences in chromosomal instability and telomere lengths are determined by additive genetic, common environmental, and specific environmental effects will be assessed using a method of robust variance component estimation (implemented in the FISHER quantitative genetics package). Collectively, the study results will enable us to make the first quantitative estimate of the proportion of acquired changes in chromosomal complements and chromosome-specific telomere length that is attributable to genetic and/or environmental factors in humans. The data from this investigation will also lead to the first direct estimate of the contribution that telomere lengths play in the formation of acquired chromosome abnormalities in humans. This information is needed for designing human mutagen and health screening tests, as well as the development of pharmacogenetic strategies to test for individual differences in susceptibility to changes in the human genome.
DESCRIPTION (provided by applicant): Developmental exposure of SNF1 mice to TCDD induces and exacerbates postnatal autoimmune lupus-like nephritis. Mechanisms that may singly or collectively underlie this environmental chemical effect on immune development will be examined, including: impaired deletion of autoreactive T cell clones in the thymus; diminished regulatory T cells that control inappropriate responses to self antigen; the forcing of T cell differentiation into extra-thymic compartments where negative selection is inefficient; a shift in the postnatal T cell repertoire toward a T helper profile and antibody production; and inappropriate B cell activity including autoantibody production. Numbers of T cells expressing autoreactive CD4+ Vbeta 17a+ and CD3+ Vbeta 3+ TcR, and numbers of CD4+25+ regulatory T cells, in extrathymic and thymic compartments, will be followed over postnatal time in SNF1 mice (autoimmune-predisposed but TCDD insensitive) and correlated to disease progression. C57Bl/6 mice (non-autoimmune but TCDD sensitive) will be used in parallel for risk assessment considerations in individuals who may be both sensitive to TCDD and genetically predisposed to autoimmune disease. In both SNF1 and C57Bl/6 mice: Con A stimulated splenic lymphocytes will be evaluated over postnatal time to identify chemical-imprinted shifts in cytokine production that may precipitate or exacerbate the postnatal autoantibody response. Antibody level to ssDNA, dsDNA and cardiolipin will be determined for comparison to cytokine profile and T helper cell activity. A focused autoimmunity gene array consisting of appropriate response genes will be used to determine the postnatal integrity of fundamental signaling pathways, proteins and downstream targets of signal transduction pathways that mediate the immune response. A reverse transcription PCR-based differential display will be used to examine thymic MHC class I and II gene expression in SNF1 and C57Bl/6 mice, with or without TCDD exposure during gestation, as a mechanism that may impair T cell education and increase peripheral autoreactive cells. The collective experiments are designed to detect alterations in fetal immune development caused by TCDD that underlie the worsened postnatal (postpubertal) autoimmune disease caused by this chemical.
DESCRIPTION (provided by applicant): The heavy metals cadmium and lead are both serious environmental contaminants that are listed among the top ten hazards by the Agency for Toxic Substances and Disease Registry (U.S. Department of Health and Human Services) based on their toxicity and prevalence in the environment. For example, lead contamination is widespread due to the ubiquitious use of lead based paints until 1978. Even recently, the USEPA estimated that 12 million homes have lead in their yards at levels exceeding the new 400 ppm standard for play areas, while 4.7 million homes exceed the new 1,200 ppm standard for the rest of the yard. Traditional means of remediation, excavation and removal of the contaminated soils, is not feasible for such a large area, but phytoremediation, or the use of plants to take up contaminants, can provide an alternative, cost-effective, method.
While plants have been identified that can tolerate high levels of toxic metals in their environment, many of these plants are unsuitable for phytoremediation based on the low amounts of biomass they produce or their limited growing range. To improve the potential for phytoremediation of metals such as lead and cadmium, the laboratory of Dr. Julian Schroeder at the University of California, San Diego, has identified two candidate genes that have been demonstrated to increase metal tolerance and accumulation in plants. The first gene, 3-ECS encodes the key enzyme in the synthesis of glutathione, an essential component in metal tolerance and the oxidative stress response. The second gene, YCF1, encodes an ABC transporter that transports glutathione metal complexes into the vacuole, sequestering the metals there and reducing cellular toxicity of the metals. These two genes will be stacked together in a single plant to test the hypothesis that they will act synergistically together and provide significantly increased tolerance. The potential of the transgenic plant for phytoremediation will be demonstrated with soil collected from contaminated sites, followed in Phase II with a field trial at one of these sites. Toxic metals such as cadmium and lead are consistently classified as among the top environmental hazards by the Environmental Protection Agency and U.S. Department of Health and Human Services, but traditional remediation methods are too expensive to address the widespread contamination. This SBIR project will develop enhanced plants that can accumulate greater levels of cadmium and lead than naturally occurring plants, allowing for removal of the metals from contaminated soil or water. These plants could lead to novel remediation technologies with reduced environmental impact than traditional solutions.
DESCRIPTION (provided by applicant): Arsenic is one of the most serious environmental contaminants in the United States. The traditional method for arsenic remediation involves excavating the contaminated soil and disposing it in hazardous waste landfills. This method is highly labor intensive and costly, especially for large sites. An alternative remediation technique is phytoremediation, the use of plants to remove toxins from contaminated soils or water and concentrate the toxins in the biomass compared to the environment. Edenspace is an industry leader in the use of plants to remediate arsenic from contaminated soil or water and has worked on numerous sites across the country. Arsenic phytoremediation currently uses an arsenic-accumulating fern plant. While this perennial tropical plant is effective is accumulating and removing arsenic from the soil, its use is limited by the need to transplant young plants rather than growing plants from seed, and by its low tolerance for sustained temperatures below -5¿C. Development of alternative crops that are more widely adapted with similar abilities to accumulate arsenic will provide enhanced capabilities to address the problem of environmental arsenic. For this STTR project Edenspace and its research partner, the University of Massachusetts (UMass) propose to develop enhanced plants for arsenic phytoremediation. A number of plant and microbial genes have been isolated and characterized that confer fourfold increases in arsenic tolerance and uptake in the model plant Arabidopsis thaliana. Because this plant has low commercial potential for remediation due to its small size, the team will bioengineer a highbiomass, non-food variety of a row crop, Brassica napus, with the transgenes. In Phase I, Edenspace will confirm that the transgenic B. napus shows the same arsenic tolerance and uptake phenotype observed in transgenic Arabidopsis, which will lead in Phase II to a small scale field demonstration. PUBLIC HEALTH RELEVANCE: Arsenic is a highly toxic substance found either naturally in the environment or concentrated by human activity at contaminated sites, and provides significant health concerns to humans and wildlife. This project intends to develop an effective and economical technology capable of removing arsenic from the environment using plants and lowering the public's risk of exposure to arsenic.
DESCRIPTION (provided by applicant)
The objective of this training grant is to train biostatisticians to work in interdisciplinary collaborative teams addressing the problems associated with explaining the effects of chemical mixtures or in the area of toxicogenomics. A key to the success of this venture is the joining of the efforts of key scientists (genomic or mixtures toxicologists, risk assessors, environmental epidemiologists and biostatisticians) in the fileds of chemical mixtures or toxicognemoics with trainees from a Department Of Biostatistics. The goal is for trainees to gain an understanding of and experience working on statistical issues for two important areas of toxicology: mixtures toxicology and toxicogenomics. These trainees will be qualified to hold unique positions in governmental agencies, academia, and industry where properly evaluating risks associated with relevant chemical exposures is becoming increasingly important.
The trainees will be Ph.D. students or postdoctoral students in the Department of Biostatistics at the Medical College of Virginia campus of Virginia Commonwealth University (VCD), where they will pursue pre- or postdoctoral training in the discipline of biostatistics. Additional expertise will be achieved through work on dissertation/research topics that are pertinent to the field of mixtures or toxicogenomics and through collaborative work with toxicologists and/or risk assessors actively working in the area of interest. Through these research projects, students will gain experience collaborating with a team of experts working on studies involving chemical mixtures or toxicogenomics. The trainees will assist in the design of studies, conduct appropriate power analyses, analyze resulting data, write reports for the preceptor with proper interpretation of the results, and participate in a collaborative team to produce one or more manuscripts for peer-review publication. In addition, the trainees will collaborate with biostatisticians who are developing statistical methodology for issues involved in the design and analysis of data resulting from chemical mixture studies or microarray studies.
BACKGROUND
This proposal reflects a continuation of an ongoing and unique training program on statistical methods for the toxicology of chemical mixtures. The proposed program incorporates a new and additional emphasis on toxicogenomics of mixtures. The proposal also adds a postdoctoral position to the program, supplementing the current five pre-doctoral trainees.
DESCRIPTION (provided by applicant)
The Environmental Mutagen Society (EMS) is the primary scientific society fostering research on the basic mechanisms of DNA repair and mutagenesis and application of this knowledge to understanding human health effects from exposure to environmental genotoxins. Studies of DNA repair and mutagenesis by EMS scientists are integrated with research on inherited and acquired genetic alterations that predispose individuals to cancer, premature aging, and other diseases. Fundamental understanding of the mechanisms and consequences of cellular, tissue, and whole organism responses to genotoxic agents is crucial to informed regulatory decision-making with respect to environmental health hazards. The integration of multi-disciplinary basic and applied research is essential to this process. Such integration remains the central focus of the EMS, and the annual meetings are key to the dissemination of information and fostering of interactions that are necessary to achieve it. In addition, the meetings provide an important forum for students and postdoctoral investigators to present their research and to interact with leading scientists in their field in a setting that encourages open exchange of ideas. The 39th Annual Meeting of the EMS will be held in Rio Grande, Puerto Rico from October 18 - 22, 2008. Its theme is "Genes and the Environment: From Molecular Mechanisms to Risk". The scientific program, which encompasses the full range of scientific interests within EMS, is comprised of symposia, workshops, topical reviews, plenary lectures, and contributed poster and platform sessions. Throughout its history, the EMS Annual Meetings have brought together academic, industrial and governmental scientists interested in how environmental factors lead to genotoxicity. Awarded funding support for the meeting is critically necessary in order to achieve this mission. The dual objectives of this conference grant application are to request funds for travel awards to students and postdoctoral fellows to attend the 2008 EMS Annual Meeting, and funds to partially support travel expenses for key non-member speakers. EMS believes that its students and postdoctoral investigators are the future of both the Society and the scientific endeavors fostered by its community of scientists. Travel awards assist in offsetting the financial burden that might otherwise prevent trainees from attending. The application also requests funds to partially defray travel costs for invited non-member speakers. EMS member speakers all agree to cover their own expenses for participation in the conference. However, it is necessary to assist with travel expenses for invited non-member speakers, who provide the cross- fertilization of ideas necessary for a world-class meeting.
DESCRIPTION (provided by applicant)
The long-term objective of this project is to protect public health by enhancing communication and scientific exchange between Environmental Health Sciences and Green Chemistry. These two emerging fields of science collectively promise to have a significant and growing impact on public health. The degree to which these two fields are able to communicate across disciplinary boundaries will not only impact each field's efficacy, but will better advance their mutual goal of building the scientific base for an economy which has human health impact at its core.
Environmental health sciences are illustrating the many intricate and subtle ways in which chemicals interfere with biological systems, including human health. Green chemistry is designing molecules, and ultimately industrial materials, which are inherently benign to human and environmental health.
Yet until very recently, there has been little direct communication between the two fields. Each has its own journals, scientific meetings and communications targeting its own membership. Yet each increasingly depends upon information and insights from the other. Environmental health provides information essential for green molecular design. Green chemistry provides new chemical solutions to systemic health problems. In recent years, individuals from both disciplines have begun to initiate working relationships. This process needs to be systematized and broadened to fully capitalize upon direct exchange between the two disciplines.
The specific aim of this project is to build a network of leaders from the two sciences that will deliberately enhance communications and cooperation across their two fields. Advancing Green Chemistry's (AGC) research design and methods to achieve this include holding a working meeting at the Beckman Conference Center at the University of California at Irvine. The meeting will consist of two parts: a public forum to introduce the two fields to a wide audience, and a private working session among the scientists to design a series of communications tools and strategies to link the fields. Following the meeting AGC will produce an article suitable for publication in a scientific journal, outlining opportunities for federal and state government investment in these scientific fields. After the meeting AGC will also build and launch on-line communications tools to aid cooperation across the sciences.
DESCRIPTION (provided by applicant)
The Teratology Society was founded in 1960 with its first annual meeting held in 1961. The Society was formed to foster exchange of information relating to congenital (birth) defects including their nature, cause, mechanism and prevention. From June 28-July 2, 2008 the Society will hold its 48th Annual Meeting in Monterey, California. The Society members and meeting attendees historically come from a diverse professional background including basic and clinical scientists from the academic, industrial and government research sectors. This rich and scientifically diverse mix of professionals, meet in an informal setting that encourages open exchange of ideas and the latest experimental findings. From its inception, the Teratology Society has understood the importance of encouraging and mentoring students and postdoctoral fellows and has included fostering education and training as part of its strategic goals. The Annual Meeting Agenda includes events and session to encourage student and postdoctoral fellow participation. For the 2008 Annual Meeting, the Teratology Society Council has developed a new mentoring program. This new program will give students and postdoctoral fellows an opportunity to have a lunch meeting with a specific leader in the Society. The event will be structured so each mentor will have small group to facilitate the participation of each attendee. In addition there will be one platform session which highlights the research of graduate students and postdoctoral fellows. This platform session is comprised of talks competitively selected from the pool of abstracts submitted for platform presentation by students and postdoctoral fellows. Those students and postdoctoral fellows whose abstracts are not submitted or selected for this session are included in other platform and poster sessions throughout the meeting. During the poster sessions, abstracts presented by students and postdoctoral fellows are marked as such in order to encourage interaction between the presenters and the members of the Society and meeting attendees.
The Teratology Society recognizes that the student and fellows are the future of both the Society and the scientific discipline. Involving the students and fellows in the science by providing them an opportunity to present their research, interact with some of the leading scientists in the field, and form relationships that they will carry throughout their career is vital to field of birth defects research. Many of these students and postdoctoral fellows rely on travel awards to assist them in offsetting the financial burden of attending the meeting. Without funding such as this, many would not be able to take advantage of the rich exchange of scientific information and new ideas generated at this scientific meeting. In this proposal, the investigators are requesting funds to defray part of the cost of travel awards. Travel awards will be granted to students and postdoctoral fellows presenting their research findings at the 2008 Teratology Society Annual Meeting.
DESCRIPTION (provided by applicant)
The American Statistical Association (ASA) Conferences on Radiation and Health provide a forum for evaluation of new methodologies and recent research findings related to the potential health risks of ionizing and non-ionizing radiation. Topics are selected by the Organizing Committee, which includes scientists with expertise in biostatistics, epidemiology, public health, biophysics and health risk assessment. Speakers are all by invitation and are internationally recognized experts in their fields of specialization. The conference is organized by the offices of the ASA in Alexandria, Virginia. The conference is attended by a highly diverse group of scientists including statisticians, health risk assessors, biologists, radiation epidemiologists, and physicists working in radiation research.
The 18th Conference on Radiation and Health is entitled, "2008 Conference on Radiation and Health, New Developments and Future Directions in Radiation Research." The Principal Investigator appointed to this project is Dr. Keith Crank, Assistant Director of Research and Graduate Education for the American Statistical Association. This funding request will provide travel assistance to new investigators.
|