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Record Count: 8
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header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant):
DNA methylation represents an important epigenetic mechanism that regulates a wide array of important biological processes. Abnormality in DNA methylation patterns is associated with various human disease conditions. In recent years, there has been a surge in research interest to address the potential modulating effect of various bioactive food components on DNA methylation, gene silencing, and reactivation. The overall objective of this application is aimed at providing systematic experimental evidence to establish a broad novel concept that many of the catecholic and noncatecholic polyphenols (e.g., tea catechins, bioflavonoids/isoflavonoids, coffee polyphenols) abundantly present in our daily diet constitute a major class of highly effective and consequential modulators of DNA methylation in vivo. This hypothesis is proposed on the basis of extensive preliminary data showing that dietary polyphenolic compounds can effectively modulate DNA methylation status in vitro and also in cultured cells. To achieve the goals, four broad-scoped but tightly-interlaced specific aims are planned to: 1) Determine in vitro inhibition of human DNMTs by various dietary polyphenols, and also study the kinetic mechanisms of human DNMT inhibition; 2) Conduct molecular modeling studies to determine the precise molecular mechanisms of human DNMT inhibition by active dietary polyphenols, and also to probe the structure-activity relationship of human DNMT inhibition by these dietary chemicals; 3) Study the effect of dietary polyphenols on DNA methylation and gene expression in human cancer cells grown in culture and in nude mice as xenografts; and 4) Study the effect of dietary polyphenols on DNA methylation, gene reactivation, and also on epigenetically-controlled phenotypes in mouse embryonic cells in culture and also in an intact animal model. It is expected that the outcomes of the proposed studies will have direct clinical utility in the near future and far-reaching human health implications.
DESCRIPTION (provided by applicant):
This research endeavor has the broad goal to develop placement methods for in-situ sediment remediation amendments. Amendments will not be developed, but research is focused upon developing the water jet design and parameters to deliver amendments that have been proven at a bench-scale. Waterjet design and parameters developed herein will specifically result in efficiency and precision in amendment placement that will allow for efficient use of newly developed amendments, which are expensive, and likely foster the research into other amendments that were though to be too expensive or undeliverable. Waterjets placement methods are already shown to have lower resuspension and harmful impact to the benthic community, and a specific objective is to further develop methods, designs and procedures to minimize these detriments even further. This project will provide direct input for scale-up and transition to field-scale testing and implementation, with design and planning stages starting within this project schedule. RATIONALE: Remediation of contaminated sediments is not currently efficient with limited options, and the basic science developing currently has a focus upon remedial amendments, yet no deliver and placement method exists for efficient engineering utilization of these amendments. Waterjet placement can be applied for a suite of amendments targeting nearly all common sediment contaminants, specifically PCBs, PAHs and redox sensitive metals. RESEARCH DESIGN: Research design is will focus on optimizing design and operational parameters at escalating scales to meet the goal listed above and will result in a field-ready technology within the project period. The assembled team has extensive experience in scale-up of basic science discovery to very large, field-scale projects and technology development and even utilization. This range of experiences and expertise is unique and will certainly help in making success in this research endeavor highly likely. RELEVANCE TO PUBLIC HEALTH: Contaminated sediments are a substantial threat to human health, tainting the base layers of the food chain. Remediation expenditures are expected to reach well into the billions, yet only three options exist. None of which truly remediate the sediment. By increasing the efficiency and lowering the cost of remediating these sites, even more sites can be truly remediated.
DESCRIPTION (provided by applicant): The 3-aminobutyric acid type-A (GABA-A) receptor is the major inhibitory neurotransmitter-gated ion channel in the central nervous system, and an important target for multiple classes of pharmacological agents including the insecticide fipronil. The insecticide fipronil is the active ingredient in many widely used pest control products, and human exposure to these agents, resulting in nausea, vertigo or seizures, has been reported in the medical literature. The proposed work will examine in detail the interactions of fipronil and its metabolite fipronil sulfone with the mammalian GABA-A receptor consisting of 11, 22 and 32L subunits. There are two aims. The first aim is to establish the kinetic mechanisms of action of fipronil and fipronil sulfone on mammalian 112232L GABA-A receptor. The second aim is to determine the mechanisms of resistance to actions of fipronil conferred by mutations in the M2 and M3 transmembrane domains. The results from the work will help to better define the mechanisms of insecticide toxicity, and may be useful in learning how to provide protection from the neurological effects of this widely used insecticide.
DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder affecting one million people in North America. There is no known cause for most cases of PD although environmental factors have been implicated in the majority of cases. We have preliminary evidence that parkinsonism is three to ten times more common in career welders than the general population. This application consists of a cohort study to test the hypothesis that the prevalence of parkinsonism is increased in a dose-dependent manner relative to non-exposed persons of similar age and gender. For our first specific aim we will perform a population based epidemiological study of the prevalence of parkinsonism in career welders and non-exposed referents. We will assemble a population based cohort of 875 workers and retirees (members of the International Brotherhood of Boilermakers) and 200 same-sex, nearest-age sibling referents with no prior welding history. Movement disorders specialists will perform all evaluations and ratings will be verified by a movement disorders specialist who will review a videotaped examination. Prevalence of parkinsonism will be compared between welders and the non-welder reference cohort. For the second specific aim of this study, an industrial hygienist will reconstruct subject welding exposure from a detailed exposure questionnaire in all exposed subjects. Subjects will be grouped into tertiles of exposure using a Job Exposure Matrix to determine if there is a dose-response relationship between welding exposure and parkinsonism. The research team represents a collaboration of movement disorders specialists, epidemiologists, industrial hygienists, and industry leaders. Demonstrating a definitive relationship between welding and parkinsonism will have substantial public health impact since the majority of these cases should be preventable through worksite modifications. The cohort assembled will provide unique opportunities for future research projects into gene-environment interactions and exposure related neuroimaging changes.
DESCRIPTION (provided by applicant): This is a second revision of a previously submitted application (R01-ES012443-01). It has recently been shown that apoptotic neurodegeneration can be triggered in the in vivo developing rodent CNS by any of several classes of drugs that have in common the property of abnormally suppressing neuronal activity. The period of vulnerability coincides with synaptogenesis, also known as the brain growth spurt period, which occurs postnatally in rodents (first 2 weeks after birth) and both prenatally and postnatally in humans (third trimester and several years after birth). Included among the offending agents are drugs that block NMDA glutamate receptors, drug that hyperactivate GABAA receptors and ethanol, which has both NMDA antagonist and GABAmimetic properties. The apoptogenic action of ethanol is a promising candidate to explain the reduced brain mass and neurobehavioral disturbances associated with the human Fetal Alcohol Syndrome. While interference with NMDA and GABAA neurotransmission during synaptogenesis is putatively responsible for much of ethanol's neurotoxic action, other mechanisms may also be operative in that ethanol kills some populations of neurons that are not affected by NMDA antagonist or GABAmimetic drugs. The applicants have recently discovered that an ethanol-like neurodegenerative syndrome can be induced in the developing rodent brain by certain solvents that are widely used in the industrial world to facilitate the manufacturing process or to dissolve and/or add functionality to marketed products, including injectable drugs used in human medicine. For example, we have found that dimethyl sulfoxide (DMSO) and propylene glycol, which are widely used throughout the world and are generally considered having a very low toxicity potential, trigger a robust neurodegenerative reaction in the developing rodent brain. This is not a property of all solvents in that polyethylene glycol, a very widely used solvent, does not display such activity. The Aims of the proposed research are to more fully characterize the neurodegenerative reactions induced by DMSO and propylene glycol, to screen other solvents for their ability to mimic this type of neurodegenerative phenomenon, to evaluate the degree of risk associated with using these agents as solvent vehicles for drugs administered intravenously to human neonates and, by a combined in vivo/in vitro approach, attempt to elucidate mechanisms underlying these newly discovered neurotoxic phenomena.
DESCRIPTION (provided by applicant): Diethylstilbestrol (DES) is the first synthetic estrogenic compound prescribed to pregnant women to prevent miscarriage. Between 1947 and 1971, more than one million U.S. women were exposed to DES in utero, which predisposed them to reproductive tract patterning defects and clear-cell adenocarcinoma of the vagina or cervix at a young age. Changes in reproductive system development have subsequently led to infertility problems for these women. Even worse, DES was introduced into the environment for its ability to accelerate cattle growth. In 1971 alone, more than 27,600 kilograms of DES were used in livestock feed lots. Unfortunately, we still know very little about the molecular mechanism by which DES affects reproductive tract development. To address this mechanism is important because many synthetic and naturally occurring chemicals we are currently exposed to also mimic estrogen and could affect the health of the next generation in a similar fashion as DES did. This proposal will dissect the genetic pathways affected by DES during female reproductive tract (FRT) development. Our preliminary studies show that several developmental control genes are regulated by DES during critical period of uterine cytodifferentiation. In particular, homeodomain protein Msx2 appears crucial in counteracting the effect of DES on the devleoping FRT as DES induces very dramatic reproductive patterning defects in Msx2 mutants, resulted from altered molecular changes in these mutants. The present grant will continue to test the hypothesis that DES can change uterine epithelial cell fate by affecting genetic pathways governing uterine cytodifferentiation. In aim 1, the role of Msx2 in uterine and vaginal development and DES-induced FRT malformations will be rigorously examined. In aim II, we will use gain and loss of function approaches in vivo to examine whether Klf4 is both necessary and sufficient for DES-induced uterine metaplasia. Finally in aim III, we will test the hypothesis that DES affects luminal epithelial architecture through modulation of the Wnt pathway. By completing these studies, we should be able to build genetic pathways controlling uterine development and address how DES can cause abnormal FRT patterning through modulation of these pathways. Our long term goal is to use mouse as a model to study reproductive tract development and how exogenous factors can influence this process.
DESCRIPTION (provided by applicant): Genetic linkage studies using various strains of inbred mice have mapped pulmonary adenoma susceptibility (Pas) and pulmonary adenoma resistance (Par) loci. However, there have been no reports on the mapping of lung squamous cell carcinoma susceptibility loci. We hypothesize that genetic modifiers for lung squamous cell tumorigenesis can be identified using F2 mapping followed by fine mapping strategies of the QTL regions. Four specific aims are proposed to accomplish our goal. In Specific Aim 1, we will conduct genetic mapping of lung tumor QTL in mice exposed to N-nitroso-tris-chloroethylurea (NTCU), a carcinogen that causes squamous cell carcinomas in mice. We propose to use the F2 progeny of the two strains of mice with extreme lung tumor phenotype (the most susceptible and the most resistant) to NTCU. Aim 2 will fine map the major QTL related to genetic susceptibility to mouse lung squamous cell carcinomas by the production of congenic strains of mice in which tumor susceptible allele is substituted onto the genetic background of the resistant mouse. The QTL will be fine-mapped by progressively reducing the QTL region through the production of sub-congenic mouse strains to narrow it to a size of around 0.5 -1 cM. In conjunction with Aim 2, we will conduct haplotype and whole-genome linkage disequilibrium analyses to fine map the major QTL in Aim 3. We have recently demonstrate the feasibility of this approach in the fine mapping and identification of candidate susceptibility genes for lung adenoma/adenocarcinomas. Aim 4 will identify the candidate gene(s) by positional cloning. DMA sequences of the narrowed region will be obtained through completed mouse genomic databases. New and known genes in the target region will be identified and candidate genes will be sought based on known or deduced function and/or differences in expression between the two parental strains of mice. The significance of these studies is that they will identify the candidate lung cancer susceptibility genes whose human homologue may predispose some individuals to lung cancer.
DESCRIPTION (provided by applicant): This application will focus on genetic susceptibility to lung adenoma induction to environmental carcinogens. Linkage analysis previously mapped a lung adenoma resistance quantitative trait locus (QTL) named pulmonary adenoma resistance 1 locus or Par1 which is located on mouse chromosome 11. The Par1 locus confers protection against lung adenoma development. Contributed by M. spretus allele, Par1 locus accounts for 23% of lung adenoma resistance phenotype to chemical carcinogens when co-expressed with highly penetrant Pas1 allele of the A/J strain. The goal of this proposal is to identify the Par1 gene, which is responsible for lung adenoma resistance to chemical carcinogens. The Par1 QTL mapping result has been confirmed by the production of congenic strains in which adenoma resistant M. spretus allele was substituted onto the genetic background of the A/J mouse. Next, the Par1 locus will be fine-mapped by progressively reducing the QTL region through the production of sub-congenic mouse strains to narrow it to a size of around 0.2-0.5 cM, which is expected to be small enough for positional cloning. DNA sequences of the entire narrowed region will be obtained through completed mouse genomic databases. New and known genes in the target region will be identified and candidate genes will be sought based on known or deduced function and/or differences in expression between A/J mice and M. spretus mice. Effect of the candidate Par1 genes on tumorigenic and growth characteristics of mouse lung cells will be examined in vitro. The functional role of the candidate Par1 gene in mouse lung carcinogenesis will be evaluated by constructing knock-in mice. The resulting knock-in mice will be subjected to lung carcinogenesis assay to confirm the Par1 gene. The significance of these studies is that they will identify the Par1 gene and facilitate our understanding of genetic basis of lung adenoma induction by environmental carcinogens.