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Record Count: 4
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):
Long term exposure to low levels of arsenic is associated with multiple diseases including skin, lung, liver, and prostate cancers, as well as metabolic disorders including hypertension and diabetes. Arsenic disrupts the regulation of genes activated by steroid hormones including those regulated by the glucocorticoid receptor (GR) that can underlie many of the same diseases as arsenic. Glucocorticoids have a role in mediating immunological and stress responses, glucose homeostasis, and cell growth and differentiation. These responses are regulated by GR-mediated gene transcription. Genes are organized in chromatin and post-translational histone modification contributes to changes in chromatin structure leading to transcriptional activation or repression. The affect of arsenic on transcription may be through disruption of cell signaling pathways that impinge on the histone acetylases, deacetylases and methylases that regulate histone modification. There is a clear link between cancer and functional disruption of these proteins with promoters.
Our hypothesis is that arsenic disrupts gene expression from steroid hormone regulated promoters by changing patterns of histone modification. GR-mediated histone modifications, acetylation and methylation, will be identified at the mouse mammary tumor virus (MMTV) promoter in the presence and absence of sodium arsenite in vivo by chromatin immunoprecipitation (ChIP) analysis (Specific Aim I). Arsenic effects on the recruitment or activity of proteins responsible for the modifications will be evaluated in cells in vivo by ChIP analysis and on assembled chromatin templates in vitro by western blot analysis. Arsenic-mediated protein modifications will be identified with radio-labeled cofactors by western blot analysis (Specific Aim II). To make a functional link between histone modifications in Specific Aim I and associated proteins in Specific Aim II with transcriptional activation, the identified proteins will be tested in cells in vivo in RNA interference (RNAi) analyses and in vitro enzyme activity assays (Specific Aim III).
DESCRIPTION (provided by applicant)
The overall objective of this Superfund Basic Research Program Project on toxic metals is to understand the human health impact of exposure to arsenic and mercury from environmental and anthropogenic sources. This program consists of three biomedical and two non-biomedical research projects, two scientific support cores, and an Administrative, Research Translation and Training Core. Projects 2 (Hamilton) and 8 (Stanton) are molecular toxicology projects investigating the molecular mechanisms by which arsenic elicits its adverse health effects, focusing on endocrine disruption and disruption of membrane protein trafficking and function, respectively. Project 7 (Chen) is an ecotoxicology project examining how mercury bioaccumulates in fish, and Project 9 is a plant biology project focusing on bioaccumulation of arsenic in rice, each focusing on how these lead to human exposures of concern. Project 4 (Karagas) is examining the human health effects of exposure to arsenic and mercury, focusing on reproductive and developmental effects in offspring of pregnant women in New Hampshire who are exposed to these toxicants via their food (arsenic and mercury) and well water (arsenic). Core B (Jackson) is a Trace Elements Analysis Core that provides state-of-the-art ultra-low level detection, quantitation and speciation of arsenic and mercury. Core E (Moore) is an Integrative Biology Core that provides comprehensive support and integration of knowledge from the project-specific molecular biology, genomics, proteomics, bioinformatics, biostatistics and modeling analysis (each provided by individual cores at Dartmouth) to the program in order to more fully understand, integrate and translate this knowledge to stakeholders. The investigators' Research Translation Core is designed to effectively facilitate this translation by assisting them in communicating the proper information in the most effective and appropriate way to each stakeholder group. The Training Core is designed to exploit their highly interdisciplinary and collaborative program in order to foster the most effective training of their students. The goal is to provide the very best science that can be used for more effective science-based risk assessments, for predicting the specific patho-physiological consequences of arsenic and mercury exposure, for assessing gene-environment, agent-agent and other complex environmental interactions, for assessing specifically sensitive sub-populations at elevated risk, and for developing effective interventions for these exposed populations.
ADMINISTRATIVE CORE (Hamilton)
Description (provided by applicant)
The Administrative Core serves as the central organizing structure for the Dartmouth Superfund Basic Research Program (SBRP). Its primary roles are to: 1) provide basic administrative support; 2) provide accounting support, pre- and post-award support, and financial oversight for the Dartmouth SBRP Program on behalf of the University and the NIH; 3) facilitate information dissemination, and serve as a central point of contact and as a communication resource; 4) serve as government liaison with the NIEHS, the EPA and other federal, state and local agencies for the purposes of effective communication and technology transfer to these agencies and other appropriate stakeholders; 5) coordinate and provide administrative support for the education and training activities of the Training Core, in collaboration with the relevant departments of the University; 6) coordinate and provide administrative support for program planning and oversight activities including the various formal and informal research, education and translation related meetings of the program; and, 7) coordinate and provide administrative support for formal Translation Core and informal translation activities; and assist in other administrative and communications activities as necessary. This office will be staffed by an Administrative/ Financial Assistant and an Office/Financial Manager who work part-time in their respective roles for this program and part-time for the Center for Environmental Health Sciences and its other research, education and translation programs; a part-time Translation Coordinator, a part-time Science Writer and a part-time Translation Assistant; and, the Director and Associate Directors of the program. The professional staff, in conjunction with the Director and Associate Directors, works through the Administrative Core to provide the cohesive structure and integration to the program. The physical offices of the Administrative Core also house all administrative functions including the administrative activities of the Training and Translation Cores, and serve as a central point of contact for all program members and those with whom the program interacts.
DESCRIPTION (provided by applicant): The primary objective of the proposed studies is to study the effects of toxicant exposures during fetal development on the adult cardiovascular (CV) system. Little is known of the etiology and progression of cardiovascular disease (CVD) in adults resulting from toxicant exposures to the pregnant mother, and the proposed studies seek to uncover early markers of disease vital in the identification of signaling pathways involved in CVD. The effect of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in CVD from fetal exposure will be examined. TCDD, the prototypical dioxin, is pervasive in the environment and causes a large number of seemingly unrelated biological effects in humans. TCDD is one of the most potent ligands for the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsible for the regulation of many detoxification genes. Because the AHR plays a role in CV development and cross talks with other signaling pathways, and because TCDD causes ischemic heart disease in the adult and induces changes in cell signaling; the intent of this proposal is to test the hypothesis that activation of the AHR by TCDD in the fetus causes a reprogramming of gene expression in the fetal CV system that results in the adult onset of CVD. To test this hypothesis, the following specific aims are proposed. (1) Determine the window of fetal TCDD sensitivity and the effect that the TCDD-activated AHR during gestation has on CVD and CV global transcription of adult progeny from mouse strains that differ at the Ahr locus. We hypothesize that the genomic and physiological effects of an acute TCDD exposure on the fetus are dependent on the activation of the AHR during particular time frames of gestation. (2) Determine the effect of the activated AHR on the CV system of adult progeny following treatment with biologically relevant doses of TCDD during gestation. We hypothesize that the genomic and physiological effects of biologically relevant doses of TCDD on the fetus play a large role in adult CVD. We expect to link gene profiles of acute- and chronic-based TCDD exposures to specific CVDs and to integrate our data sets with other gene profiling data sets. The results will lead to a clearer understanding of the mechanisms that are initiated from fetal exposures that lead to adult disease, and with such knowledge, preventative measures can begin to be implemented to protect mother and fetus.
DESCRIPTION (provided by applicant)
Project Summary: The impact of the built environment on health in rural areas has been understudied and virtually nothing is known about the influence of the rural built environment on overweight in adolescents. Our overarching goal for this study is to examine the influence of the built environment on adolescent overweight in the predominantly rural communities of Northern New England. Our multidisciplinary team will use quantitative and qualitative methods to conduct multi-level assessments of risk factors for adolescent overweight. We will accomplish our aims by studying an established cohort of 2567 adolescents and their parents, representing 26 stable and largely rural communities in Vermont and New Hampshire. When adolescents (8-13 years of age) were first surveyed in 2002-2003, the prevalence of overweight by community ranged from 9.7% to 34.1%, indicating substantial variation at the community level. Relevant individual and family characteristics of this cohort will be assessed through three annual telephone surveys, beginning in January 2006. We will use GIS data and on-site mapping, to characterize the built environment of each community. The community level data will include assessments of recreational resources and food (including fast food) availability, as well as standard measures of density, diversity and design. We will use an ethnographic approach to assess and describe the 'culture' surrounding physical activity and food within each of the schools attended by our cohort. The assessment of multi-level data will allow us to investigate how individual and family characteristics interact with the built environment to influence adolescent overweight. Our primary outcome will be adolescent overweight (defined as body mass index (BMI) equal to or greater than the 95th percentile of the sex-specific BMI-for-age growth curves. Intermediate outcomes will include adolescent physical activity levels and dietary intake patterns, including consumption of high fat and high calorie foods. The multi-disciplinary expertise of our investigative group and the availability of a well-established cohort ensure the feasibility, efficiency, and success of the proposed effort. Relevance: Our study includes children and low SES communities, two populations targeted by RFA-04-003 because of their vulnerability. In addition, our study focuses on rural communities, meeting the expressed need for studies of rural populations. Results from this study will help to identify risk factors that could be targeted through specific interventions to prevent adolescent overweight.
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