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Record Count: 33
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header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant): The main focus of this proposal is investigation of the concept that functional variation in the DNA repair gene XRCC1 can influence susceptibility to carcinogen-induced tumorigenesis. XRCC1 has been shown to be a key player involved in base excision repair, single strand break repair, and possibly double strand break repair. A number of XRCC1 polymorphisms have been identified, and cancer association studies have received extensive epidemiological attention but with conflicting results. In order to help validate the important biological role of DNA repair and specifically XRCC1, in environmental carcinogenesis we are proposing to use mutant mouse models representing human haploinsufficiency and polymorphisms. XRCC1 has no known enzymatic activity, but depends on protein to protein interactions to carry out its functional role in DNA repair. Therefore, use of a biological system such as the mouse to help define function related to expression of an observable tumor phenotype when challenged with a carcinogen is a major means of investigating XRCC1 function. Azoxymethane (AOM) is an alkylating agent and a well-established carcinogen in mice with a spectrum of pre-tumor, pre-malignant, and malignant lesions in the colon and to a lesser extent the liver. It also serves as a prototype for alkylating agents present in the environment that present potentially significant exposure risks. Our hypothesis is that cancer susceptibility to AOM can be influenced by XRCC1 haploinsufficiency and single nucleotide polymorphisms R194W and R280H. Information generated from our proposed studies could be used to help design clinically relevant studies to identify individuals or groups that may be at increased cancer risk for specific environmental conditions. PUBLIC HEALTH RELEVANCE: The main focus of this proposal is investigation of the concept that functional variation in the DNA repair gene XRCC1 can influence susceptibility to carcinogen-induced tumorigenesis. XRCC1 has been shown to be a key player involved in base excision repair, single strand break repair, and possibly double strand break repair. A number of XRCC1 polymorphisms have been identified, and cancer association studies have received extensive epidemiological attention but with conflicting results. In order to help validate the important biological role of DNA repair and specifically XRCC1, in environmental carcinogenesis we are proposing to use mutant mouse models representing human haploinsufficiency and polymorphisms.
DESCRIPTION (provided by applicant):The broad objective of this proposal is to
understand the molecular details of an important defense mechanism (DNA
excision repair) against mutations and phenotypic changes in human cells. Such
changes are important etiological factors in cell survival and cancer. Bulky
DNA lesions result from a plethora of environmental agents, such as ultraviolet
(UV) radiation and chemical carcinogens, and repair of these lesions occurs by
nucleotide excision repair (NER). As the same repair process is used for
removing the majority of these bulky lesions, UV radiation will be used as a
prototype environmental agent for these studies.
We will study histone modifications during NER at damaged DNA sites in human
chromatin by tagging nascent and mature repair sites with nucleotide analogues
for isolating these regions as protein-DNA complexes, by chromatin
immunoprecipitation (ChIP) with specific modified histone antibodies, and by
examining the effect of histone deacetylase inhibition on NER and maturation of
nascent repair sites in human cells. Secondly, we will examine NER of single UV
damaged sites strategically located in a transcription factor complex by
analyzing the effect of single UV photoproducts (CPDs) at strategic sites on
complex formation, by examining NER of CPDs at strategic sites in this complex,
and by examining displacement of the transcription factor during NER. Thirdly,
we will examine NER at UV damaged sites in oligonucleosomes in a cell free
repair system by analyzing the effect of packaging DNA into oligonucleosomes on
repair of CPDs, by analyzing the effect of NER of CPDs on the packaging of DNA
into oligonucleosomes, and by analyzing the effect of histone acetylation in
oligonucleosomes on repair of CPDs. Finally, we will explore the potential of
chromatin remodeling activity having a role in NER at UV damaged sites by
analyzing the accessibility of CPDs in model chromatin substrates following
reaction with nucleosome unfolding complexes in vitro, by measuring mitotic
viability and metabolic competence in two classes of UV irradiated yeast
mutants with deficiencies in chromatin remodeling, and by examining NER in two
classes of yeast mutants with deficiencies in chromatin remodeling.
Thus, we will use a 'multifaceted" approach to examine the role of chromatin
structure in DNA repair with the ultimate goal of understanding this process in
human cells. Since DNA lesions may alter the expression of specific genes
required for establishing the neoplastic phenotype, these studies should
provide valuable insight into the cell's defense mechanism for resisting
neoplastic transformation by environmental carcinogens.
DESCRIPTION (provided by applicant): The overall aim of this proposal is to establish an integrated Center for creating high-quality reference maps of key epigenotypes in pluripotent, differentiating, and primary differentiated human cells and tissues. The Northwest Reference Epigenome Mapping Center aggregates leading experts in human embryonic stem cell (hESC) biology, lineage-specific differentiation of hESCs, and well-established differentiating and differentiated adult primary tissue systems to establish a substantial capacity for the production of purified cells and tissues for large-scale epigenomic studies. The Center integrates this capacity with an existing high-throughput genomics and informatics infrastructure operating at scale, creating unique synergies that enable genome-scale epigenetic analyses of high-value human primary and progenitor cell types. The Center will perform high-resolution, whole-genome profiling of foundational epigenotypes in project cell types including high-resolution quantification of chromatin structural remodeling, and analysis of DNA methylation at both actively remodeled and silenced regulatory DNA templates. The Center will also profile both small RNA species and conventional gene expression from all study cell types. The Center's informatics and analytical arm will manage project data and its release into consortium and public repositories, and will perform integrative analyses to elucidate the connection between major epigenotypes and dynamic cellular programming of gene expression.
DESCRIPTION (provided by applicant): Polychlorinated biphenyls (PCBs) have been implicated as potential carcinogens, particularly in studies of non- Hodgkin's lymphoma. PCBs remain a public health concern despite ceasing production, because of bioaccumulation in the food chain and their presence in adipose tissue of virtually every person. PCBs and other organochlorines find a stable reservoir in fat; however, they are excreted to the bloodstream with lipid mobilization during times of negative energy balance, such as weight loss. This process of organochlorine mobilization exposes cells and tissues to increased concentrations of PCBs, thereby creating a window for enhanced toxicologic effects. Aims of this study are to investigate associations between exercise-induced weight loss, PCB concentrations, and immune function among postmenopausal women. The proposed study builds on resources from an existing randomized controlled trial of exercise with an extensive assessment of immune function biomarkers. Subjects are postmenopausal women (Seattle, USA) who participated in a one- year randomized trial to study biologic effects of exercise. In the proposed study, we will measure PCB concentrations in plasma samples from 100 subjects (50 intervention arm, 50 controls) both prior to the intervention and at a 12-month follow-up visit. Data on PCB concentrations and existing trial data will be used to: 1) Evaluate relationships between energy balance characteristics and plasma PCBs, both prior to the intervention and across the trial period; and 2) Investigate immune effects of PCB exposure, both prior to the intervention and following any changes in PCB concentrations that result from the exercise intervention. We will explore how circulating PCB concentrations are associated with specific aspects of energy balance such as weight and weight cycling history, body composition including abdominal adiposity, and changes in weight and body composition during the intervention. Additionally, the study design will allow investigation of how PCB 'dose' resulting from weight loss during the trial affects immune function measures such as lymphocyte phenotypes, natural killer cell cytotoxicity, and lymphocyte proliferation. We hypothesize that the exercise intervention will be associated with increases in plasma PCB concentrations, and that PCB increases will be most pronounced among women with the greatest body fat loss. Furthermore, we hypothesize that increases in PCBs during the trial will be correlated with decreased lymphocyte proliferation and other markers of immune function. The proposed study represents a unique opportunity to expand the state of knowledge about energy balance, organochlorine exposure, and possible toxicologic effects by studying these relationships in a population-based sample of healthy women, within an existing framework of a randomized trial with rich data resources. The proposed project will describe associations of changes in weight and/or body composition with organochlorine exposure, and will investigate immune effects of polychlorinated biphenyl (PCB) exposure before and after weight loss. The study has significant relevance to public health because of both the growing problems of obesity and weight cycling in the United States and the ubiquitousness of PCB pollution. Understanding possible toxicologic effects of organochlorine exposure following weight loss may provide clues about certain detrimental effects of energy imbalance.
DESCRIPTION (provided by applicant): The number of adults affected by asthma in the United States has grown dramatically in the past two decades and asthma now affects 14 million adults. Control of asthma is inadequate for many of them, leading to substantial morbidity and economic burden. The primary goal of our proposal is to develop and assess the value of a home-based education and support intervention called HomeBASE (Home-Based Asthma Support and Education) for reducing asthma morbidity among low-income, ethnically diverse adults with asthma ages 18-65. The value of an in-home intervention, while effective among children with asthma and theoretically appealing, has not been assessed among adults. Specifically, the project will test the hypothesis that community health workers providing education and support for self-management of asthma, assessment of the home for environmental triggers, resources for asthma control, and assistance in effective communication with medical providers over the course of one year will reduce asthma morbidity, asthma- related urgent health care use and exposure to indoor asthma triggers. A randomized controlled trial using participatory research methods will be used. Four hundred twenty participants will be enrolled and followed for two years. Primary outcomes include asthma symptom-free days, asthma-related quality of life and urgent health service use. Full data will be collected in person at baseline, and one and two years later. Interim data will be obtained through telephone interviews. Exposure to asthma triggers will be assessed through interviews, home inspection and analysis of house dust for mite allergen. The incremental cost- effectiveness (dollars per symptom-free day) will be measured. Other aims include (1) ensuring community participation in study design, implementation, evaluation and dissemination and (2) and disseminating protocols and tools for program replication should HomeBASE prove successful. The proposal was initiated by and is sponsored by the King County Asthma Forum, the local asthma coalition. It has been developed through existing collaborative relationships among partners who are members of the HomeBASE Steering Committee: people with asthma, private sector clinics and hospitals, community clinics, the local public hospital, the local health department, community-based organizations and the University of Washington. The Community Advisory Group, consisting of people with asthma, has advised on proposal development.
DESCRIPTION (provided by applicant)
The theme of this Center is "Biochemical and Molecular Mechanisms Underlying Human Variability in Response to Environmental Exposures". The interactions between genetics and environment are complex, and defy explanation through traditional disciplinary pathways of investigation. The purpose of this NIEHS Center is to provide an administrative infrastructure and technical support to foster the multidisciplinary collaborations necessary to extend basic mechanistic studies on environmental health problems to direct application in human populations. This center consists of 6 research cores: 1) Gastrointestinal and Renal Toxicology, 2) Carcinogenesis, 3) Reproductive and Developmental Toxicology, 4) Neurotoxicology, 5) Cardiovascular Respiratory Toxicology, and 6) Bioinformatics and Biostatistical Methodologies. Each of these Cores consists of 7 - 10 senior investigators and 2 - 5 associate investigators representing several different departments and programs throughout the University. The funded research of these core faculty is enhanced by 5 Facility cores which provide Center investigators access to: 1) Functional Genomics, 2) Functional Proteomics, 3) Analytical Cytology, techniques such as flow cytometry and fluorescence activated quantitative cytometry, 4) Transgenic Animal Services, support for development and maintenance of transgenic animals of value in toxicological research, and 5) Bioinformatics and Biostatistics, provides guidance for research statistical data. The Pilot Projects support five exploratory research projects into innovative new ideas related to the theme of the Center for one year. A Community Outreach and Education Core provides a mechanism to disseminate important research findings of Center investigators to the general community, as well as a coordinating function to extend and enhance existing community education programs to include more emphasis on issues related to environmental health sciences. The Ethical, Legal and Social Issues (ELSI) Core provides the researchers with the latest information dealing with these issues.
DESCRIPTION (provided by applicant)
The theme of the Pacific Northwest Center for Human Health and Ocean Sciences is elucidation of the mechanisms that govern relationships between marine processes and public health consequences of harmful algal blooms. Consistent with RFA ES-03-003, the investigators have designed a multidisciplinary research team including faculty from several academic institutions and departments in partnership with state and federal governmental organizations to facilitate both mechanistic and applied research on production and adverse affects of harmful algal blooms. The proposed Center will be a joint collaboration effort between two top-rated academic programs, the University of Washington Schools of Oceanography, Marine Affairs, and Aquatic and Fishery Science within the College of Ocean and Fishery Science and the Department of Environmental and Occupational Health Sciences (DEOHS) in the School of Public Health and Community Medicine. Also participating, both financially and with shared expertise, are investigators from the National Atmospheric Administration (NOAA), Washington State Department of Health, Washington State Department of Ecology, the Institute for Systems Biology, and the University of Maryland. The premise underlying this research is that genetic and environmental variability defines the toxicity and dynamics of harmful algal blooms (HABs), the retention of the toxin by shellfish and the human populations that are susceptible to toxicological impacts. The theme of this Center emphasizes the importance of understanding and characterizing environmental conditions and forces that determine the development of HABs and the factors that determine human susceptibility to risk associated with exposure to these. This is responsive to the directives in the NSF and NIEHS sponsored roundtable on Oceans and Human Health.
Crisp Terms/Key Words: environmental exposure, marine toxin, saltwater environment, algae, public health, seafood poisoning, clinical research
DESCRIPTION (provided by applicant)
This application is for a five-year competing renewal of the University of Washington (UW) Superfund Basic Research Program Project. The theme of this Program Project is that biomarkers measured in accessible tissues are predictive of: a) toxicant exposures; b) early indicators of damage; and/or c) unusual susceptibility to toxic agents that commonly occur at hazardous waste sites. The proposed UW Program includes 5 research projects (biomedical and ecological/bioremediation), an Administrative Core, a Research Translation Core, a Functional Genomics and Bioinformatics Core, and an Outreach Core. The Program will focus most intensively on biomarker applications for investigations of adverse effects to human health and the environment from neurotoxic chemicals, primarily metals and pesticides. Collectively, these projects will develop and validate biomarkers for elucidating underlying neurotoxicity mechanisms, characterizing risks to humans, animals, and the environment, identifying host susceptibility traits that modify exposure/risk relations, and for implementing phytoremediation techniques. The research projects include studies of: 1) investigations of genetically-determined susceptibility factors predictive of mercury-related neurobehavioral impairment in children and adults; 2) animal models of susceptibility to organophosphate pesticides, with applications to human Parkinson's disease (PD); 3) environmental and genetic determinants of Parkinson's disease; 4) sub-lethal neurotoxic effects of metals and pesticides in free-living Coho salmon; 5) phytoremediation methods for organic solvents and pesticides. The Functional Genomics and Bioinformatics Core will provide extensive molecular biology laboratory and data analysis support to all research projects. Multidisciplinary collaborations among scientists specializing in neurotoxicology, epidemiology, molecular genetics, and bioinformatics will be emphasized as an essential feature of this highly integrated research program. The Administrative Core, directed by the Program Director, will oversee all major budgetary and personnel aspects of the Program Project, and will coordinate multidisciplinary interactions among research projects and cores. An External Science Advisory Board, composed of scientists from academia and government agencies, and an Internal Executive Committee that includes the Program Director, the Deputy Director, and selected program investigators, will provide scientific advice and oversight. The Research Translation Core will be responsible for communicating our research findings to community, government, and private sector stakeholders. This Core will also supervise technology transfer activities. The Outreach Core will coordinate efforts with the Research Translation Core to ensure appropriately tailored dissemination of research findings to community groups, government agencies, health professionals, and the broader scientific community.
DESCRIPTION (provided by applicant): The potential effects of man-made substances on the reproductive health of humans and other animal species is an area of increasing concern, however, efforts to clearly delineate the reproductive effects of specific substances have been hampered by the lack of a suitable assay system. The inadvertent exposure of mice in our colony to bisphenol A (BPA) during the course of meiotic studies provided evidence that this "estrogen mimic" disrupts mammalian female meiosis, increasing the risk of meiotic nondisjuntion. Subsequent investigations in our laboratory suggest that the meiotic process in both male female mice is exquisitely sensitive to BPA, as doses that are 1000-fold lower than the currently accepted NOEL induce detectable meiotic abnormalities. These findings raise serious concerns about the potential reproductive effects of BPA on humans. However, effective studies in humans can best be designed if we first accurately define the effects of BPA exposure in an animal model. The proposed studies are designed to explore these preliminary findings in depth, allowing us to determine how, when, and at what level of exposure BPA acts to disrupt mammalian meiosis during both oogenesis and spermatogensis. Importantly, we will determine whether other estrogenic compounds (e.g., estradiol, diethylstilbesterol) elicit similar effects and thereby begin to elucidate the cellular/molecular mechanisms of BPA action. Further, we will use estrogen receptor knockout mice to test the hypothesis that apparent BPA-specific meiotic effects are mediated through non-traditional mechanisms (i.e., act independently of the known estrogen receptors). Lastly, we will use a newly devised screening tool involving the budding yeast, Saccharomyces cerevisiae, to determine the mechanism(s) by which BPA exerts its effects. The combined data from these studies will not only provide important insight concerning the potential effects of BPA exposure in humans, but will test the efficacy of meiotic studies in assessing the reproductive effects of chemical exposures.
DESCRIPTION (provided by applicant): The goal of this project is to identify additional genes for inherited predisposition to breast cancer by studying families and patients of Ashkenazi Jewish (A J) ancestry. Several groups of people will be evaluated: ~60 AJ families with high incidence of breast cancer, ~900 unselected AJ breast cancer patients, ~100 AJ control families, and >3000 AJ population controls. The families and patients are wildtype by multiple tests at all known genes for inherited breast cancer. The proposed experimental and analytic approach is based on the distinctive historical demography of this 3opulation and combines linkage within families, haplotype sharing across families, resequencing candidate genes, and comparison of variant allele frequencies in independently ascertained cases vs. controls. This approach was validated by the identification of a previously undetected allele of CHEK2 co-segregating with breast cancer in a subset of these AJ families, then the demonstration that this allele was significantly more frequent among the AJ breast cancer cases than among AJ controls. Functionally, whereas wildtype human CHEK2 complemented the lethality of a Rad53 deletion in yeast, the mutant allele failed to do so. Most familial breast cancer remains unexplained by inherited mutations in BRCA1 or BRCA2 or other susceptibility genes. Discovery of additional breast cancer genes of moderate penetrance in the AJ population will be important to women both in this population and generally.
DESCRIPTION (provided by applicant): Organophosphate (OP) acetylcholinesterase inhibitors are used widely in agriculture as pesticides and also have been used in terrorist attacks against civilian populations. OPs are irreversible acetylcholinesterase inhibitors which can cause death due to overstimulation of both central and peripheral cholinergic systems. Overstimulation of muscarinic acetylcholine receptors (mAChR) in the central nervous system (CNS) can cause respiratory depression and convulsions. This research will use genetic, pharmacological, and molecular approaches to define underlying mechanisms of OP action in the CNS and to identify new pharmacological targets to prevent or ameliorate OP-induced actions in the CNS. OP-induced seizures progress through three neurochemical stages: an initial phase which can be blocked by muscarinic antagonists, followed by a transitional period where both cholinergic and noncholinergic pathways contribute to the seizures, and followed by mainly noncholinergic-mediated seizure activity. This proposal will use mouse strains deleted of specific mAChR genes to determine the subtype of receptor which mediates OP-induced convulsions. This proposal will also use pharmacological and genetic approaches to determine the roles of the noradrenergic and dopaminergic systems and their receptors in OP-induced seizures. Prevention and/or termination of OP- induced seizure activity is critical both for reduction of rapid lethality and pathological neurological changes. The cell damage after OP-induced seizures is followed by proliferation of neuronal precursor cells. This increased neurogenesis has been suggested to both contribute to and to limit the long-term damage caused by OP exposure. This proposal will also determine the mechanisms and contributions of convulsive and non- convulsive pathways to OP-induced cell death and neurogenesis. Environmental exposure to OP pesticides causes thousands of death world-wide. The dangers of the use of OP nerve agents in attacks on civilian populations was demonstrated by the sarin attacks in Japan in 1994 and 1995 which resulted not only in immediate deaths but in changes in long-lasting neurological functions. This research will provide valuable new insights into the mechanisms of OP action in the CNS and identify new potential targets for specific pharmacological interventions to ameliorate the effects of OP on the CNS. PUBLIC HEALTH RELEVANCE Organophosphates are inhibitors of the nervous system enzyme acetylcholinesterase inhibitors and are used widely in agriculture as pesticides and also have been used in terrorist attacks against civilian populations. Exposure to organophosphates can cause convulsions and long-term damage to the central nervous system. This research will determine the molecular mechanism for these actions and may identify targets for improved treatment of organophosphate poisoning.
DESCRIPTION (provided by applicant): Although the etiology of Parkinson's disease (PD) has not been defined, epidemiological studies have indicated a correlation between increased risk for PD and occupational exposure to pesticides including paraquat, a widely used herbicide. Interestingly, treatment of mice with paraquat produces many key features of PD including dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc) of the brain and formation of 1-synuclein containing inclusion bodies. Therefore, studies of paraquat-induced dopaminergic neuron death may provide important new information concerning mechanisms governing the death and survival of dopaminergic neurons and thereby provide important new insights concerning the molecular basis of PD. Recently, we discovered that paraquat selectively kills dopaminergic neurons in primary cultures by a mechanism that requires activation of the c-Jun NH2-terminal protein kinase (JNK) and JNK-induced gene expression. Furthermore, paraquat-induced dopaminergic neuron death is inhibited by bFGF. This proposal is based upon the hypothesis that JNK, specifically the neurospecific JNK3 isoform, plays an important role in paraquat-induced death of dopaminergic neurons, and that this cell death may be mediated by BimEL and antagonized by bFGF. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in the paraquat model of PD. Furthermore, our proposed research meets the goals of NIEHS strategic plan, especially to "support research that improves our understanding of signal transduction pathways and their influence on disease" under goal #2, which is to "use environmental toxicants to understand basic mechanisms in human biology". PUBLIC HEALTH RELEVANCE Parkinson's disease is the second most common aging-related neurodegenerative disorder. We propose to elucidate molecular mechanisms underlying paraquat-induced dopaminergic neuron death in vitro and in vivo. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in the paraquat model of Parkinson's disease, and may provide important new insights concerning the molecular basis Parkinson's disease.
DESCRIPTION (provided by applicant): Parkinson's disease is a common age-related neurodegenerative disease characterized pathologically by a loss of dopaminergic neurons in the substantia nigra with resultant depletion of striatal dopamine and presence of Lewy bodies in the remaining neurons. Lewy body contains numerous functional and structural proteins, including alpha-synuclein and ubiquitin, and aggregation of alpha-synuclein is thought to be important in Lewy body formation as well as neurodegeneration, although the detailed mechanisms remain to be defined. Increasing evidence has suggested that mitochondrial dysfunction, increased oxidative stress and dysfunction of the ubiquitin-proteasome system may be involved in Lewy body formation as well as neurodegeneration. A few neurotoxicants, e.g. rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, all capable of inhibiting mitochondria and enhancing oxidative stress, have been utilized widely to generate parkinsonian models in vitro and in vivo. Interestingly only rotenone produces Lewy body-like cytoplasmic inclusions. On the other hand, there are also human nigral degenerative diseases with or without Lewy body formation in the substantia nigra, including Parkinson's disease, dementia with Lewy body disease and multiple system atrophy. Our preliminary studies in cell cultures demonstrated that proteins interacting with alpha-synuclein may influence alpha-synuclein aggregation, Lewy body formation and cell death. Hence, this application proposes to advance our understating of the development of Lewy bodies as well as molecular mechanisms of development of Parkinson's disease with subtractive proteomics by looking for differences in the proteins associated with alpha-synuclein in the substantia nigra between rotenone-exposed and control rats first, and then comparing the protein profiles in rotenone-exposed rats vs. rats exposed to 1- methyl-4-phenylpyridinium, the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, or 6- hydroxydopamine. A second phase would examine tissues from patients with Parkinson's disease vs. controls as well as patients with multiple system atrophy. Finally, we will study the roles of the common and differentially displayed proteins, those related to oxidative stress, mitochondrial and proteosomal function in particular, in alpha-synuclein aggregation, Lewy body formation and neurodegeneration.
DESCRIPTION (provided by applicant): Environmental toxicants including pesticides may contribute to the development of various neurodegenerative disorders including Parkinson's disease (PD). One of the mechanisms implicated in various neurodegeneration is neuronal apoptosis. We discovered that chlorpyrifos and rotenone both stimulate apoptosis in neuronal cells, suggesting that pesticide-induced apoptosis may play a role in neurodegeneration. Consequently, it is important to elucidate molecular mechanisms for induction of apoptosis by pesticides in neurons. The overall objective of this project is to elucidate apoptotic mechanisms for chlorpyrifos- and rotenone-induced apoptosis in neurons. Chlorpyrifos, an organophosphate pesticide, is one of the most commonly used pesticides. Its primary target of toxicity is the CNS. Treatment of rats with rotenone, a common insecticide, causes all PD symptoms. Therefore, chlorpyrifos and rotenone, two distinct classes of pesticides, are chosen as models to study pesticide-induced neuronal apoptosis. Our preliminary data suggest that both chlorpyrifos and rotenone induce apoptosis in primary cultured cortical neurons and SH-SY5Y cells. They also activate the stress-activated MAP kinases, JNK and p38. We hypothesize that activation of these kinases is important for chlorpyrifos- and rotenone-induced apoptosis in neurons. We will test this hypothesis and elucidate downstream mechanisms by which chlorpyrifos and rotenone stimulation of JNK and p38 causes neuronal apoptosis. This study should provide valuable new information concerning the molecular basis of pesticide-induced apoptosis in neurons and new insights concerning the role of environmental toxicants in neurodegeneration.
DESCRIPTION (provided by applicant): Preeclampsia and preterm delivery are important causes of maternal and infant morbidity and mortality. Recent studies suggest that elevated air pollutant exposures may lead to preterm delivery, even at air pollutant levels typical of those in many US cities. No prior studies have directly examined air pollutant exposure in relation to preeclampsia; although much evidence suggests that the relation is biologically plausible. This study is based on a source population of women participating in a large cohort study. Participants enroll during early pregnancy and are followed until delivery. We will design models that use local traffic, weather, and population characteristics to predict monthly ambient concentrations of fine particulate matter (PM2.5) and carbon monoxide (CO). These models will be used to estimate study participants' PM2.5 and CO exposures before and during pregnancy. We will test whether these air pollutant exposures are associated with subsequent risk of preeclampsia and preterm delivery using multivariable logistic regression procedures. Additionally, we will test biological markers of maternal lipid peroxidation (thiobarbituric acid reactive substances) and inflammation (high sensitivity C-reactive protein) in maternal blood samples drawn during early pregnancy. We will use multivariable regression to examine lipid peroxidation and inflammation as biological mechanisms in air pollutant/disease relationships. We will also examine carboxyhemoglobin measured in early-pregnancy maternal blood samples as a marker of CO exposure. We will test the associations between carboxyhemoglobin and the pregnancy outcomes. Study results could contribute to knowledge regarding the causes and mechanisms involved in preeclampsia and preterm delivery. Such knowledge may have significance in developing preventative interventions for these two common adverse outcomes. The results could also contribute to the body of heath-related science that influences air quality standards and policies.
DESCRIPTION (provided by applicant): The contribution of diesel exhaust (DE) to health, especially children's health, is of tremendous public health interest. DE has been associated with worsening asthma and allergies, among other important health effects. Reducing DE exposures has become a major regulatory initiative, and federal, state, and local jurisdictions are investing hundreds of millions of dollars in retrofitting diesel engines in school buses and other changes to reach this goal. However, a serious question remains unanswered: what magnitude of impact will this major governmental environmental policy have on public health, especially the health of asthmatic children who commute by diesel bus? This proposed study fills in the knowledge gap and provides substantial public health information on the impact of such regulations and nationwide changes by examining the importance of DE exposures to asthma morbidity among children who ride school buses, while adjusting for the influence of ambient air pollution and other factors that change over time. This 5-year study will be the first to assess children's health effects from DE before and after the change from "dirty" to "clean" engines and fuels in school bus fleets. This project aims to: 1) determine whether asthmatic children changing to buses with cleaner fuels and engines have a reduction in sub-clinical and clinical asthma severity; 2) determine if increased levels of DE exposure lead to an increase in clinical features of asthma; and 3) quantify and characterize the changes in particle and toxic gas exposures to DE in asthmatic children. This study includes 3 years of exposure and health monitoring on 500 asthmatic school children who commute to school in the Puget Sound area of Washington State. Monthly measures of pulmonary function using spirometry, pulmonary inflammation assessed by exhaled nitric oxide, asthma symptoms, medications, and clinical encounters, will be obtained on all children during the school year. The 500 children will be recruited from several school districts to represent 3 exposure scenarios: 1) 125 children riding retrofitted diesel bus or commuting by car over all years of study; 2) 250 children riding old diesel buses, which will be retrofitted after the first and second year of the study; and 3) 125 children riding old diesel buses throughout the study. Exposures will be estimated for all subjects, and an in-depth individual exposure assessment will be performed on a subset of 144 subjects and 48 school buses in each monitoring year to cover the spectrum of bus type and routes. These personal exposure measurements will be used to characterize and distinguish children's exposure to DE from other sources, and develop an exposure model for those who are not personally monitored. This study will provide critical missing information relating reductions in diesel emissions directly to reductions in exposures and health effects.
DESCRIPTION (provided by applicant): There is increasing evidence in the scientific literature that there are adverse health effects associated with levels of ambient air pollution that fall within the current standards, especially for populations with chronic respiratory diseases. Children and adults with cystic fibrosis (CF) are an at-risk population for which the health effects of ambient air pollution have not previously been investigated. Identifying environmental risk factors for the progression of pulmonary disease in the cystic fibrosis population may contribute to better understanding of this complex heterogeneous nature of this disease. Our objective is to assess and clarify the association between air pollutants and CF lung health and mortality among U.S. CF patients. Information concerning the impact of environmental factors on cystic fibrosis is limited. We recently completed a preliminary cohort study to assess the impact of air pollutants in cystic fibrosis. The study included patients over the age of 6 years enrolled in the Cystic Fibrosis Foundation National Patient Registry in 1999 and 2000. Exposure was assessed by linking air pollution values from the Aerometric Information Retrieval System with patients' home zip code. We found that after adjusting for confounders, a 10 ¿g/m3 rise in course particulate matter (PM10) and fine particulate matter (PM2.5) was associated with an 8% (95% CI 2-15%) and 21% (7-33%) increase in the odds of two or more exacerbations, respectively; a 10ppb rise in ozone was associated with a 10% (3-17%) increase in odds of two or more exacerbations. We also found that for every increase in PM2.5 of 10 ¿g/m3, there was an associated fall in forced expiratory volume in 1 second (FEV1) of 24 ml (7 - 40) after adjusting for confounders. Given this finding, we evaluating the impact of longer term exposure to ambient air pollution on lung function and mortality in CF. We found a strong association between ambient air pollution and lung function as measured by FEV1. Increased PM2.5 and PM10 was associated with lower lung function. Given this data, it is critical to understand whether air pollution affects lung growth in CF patients, given the relationship between lung function and survival in CF. We propose to first model lung growth in CF based on mixed effects multivariate regression models of FEV1 and forced vital capacity (FVC) in children ages 6-18 with cystic fibrosis from 1994-2005. We will then assess the impact of ambient air pollution (as assessed by average annual exposure) on lung growth. Lastly, we propose evaluating the impact of different methodologies of exposure (ambient air pollution) modeling on the impact of air pollution on lung growth in CF. As CF researchers search for gene modifiers in CF disease to better understand the pathophysiology of CF lung disease and identify new potential therapies, it is critical to understand how important environmental exposures are in the course of the disease. Our proposal work may contribute to a better understanding of the role of environmental factors on cystic fibrosis (CF) outcome and prognosis and also could add to the growing body of evidence regarding the health effects of air pollutants on susceptible and at risk populations. Our proposal will also enhance our understanding of lung growth in CF and represents the initial phase of a program to understand environmental effects on CF lung disease.
DESCRIPTION (provided by applicant): The overall objective of this project is to further our understanding about the sources of outdoor air pollution that are detrimental to human health. Observational approaches to investigating effects of air pollution typically employ measurements of outdoor air pollutant concentrations obtained from one or more pollution monitors used to reflect pollutant exposures in a large urban area. Findings from studies that use ambient air pollutant concentrations to specify exposure are often difficult to interpret. An alternative approach is to attempt to measure effects associated with specific sources of air pollution. We propose to apportion sources of air pollution through detailed analyses of air pollution monitor filters and a factor analysis approach in order to address the following hypotheses: 1. A source-oriented approach will identify one or more ambient pollutant sources that contribute to short-term adverse health effects. Specifically, a source-oriented approach will identify an association between motor vehicle emissions and adverse health effects. 2. Use of a multivariate, "receptor-based" approach is a valid approach to identifying pollution source contributions to the ambient pollution mix in a large urban area.
The primary hypothesis (1) will be tested by investigating the daily occurrence of several health outcomes in the Denver metropolitan region in relation to short-term changes in air pollution exposure specified by the source-oriented approach and the traditional approach using only air pollutant concentrations. The health outcomes to be studied include daily mortality, daily hospitalizations in the elderly with respiratory and cardiovascular diagnoses, daily emergency room visits to Denver area hospitals for selected respiratory and cardiovascular illnesses, and daily measures of asthma control in a sample of asthmatic school children.
Attempts to control air pollution for the purpose of protecting public health are hampered by the limited information available on the sources of air pollution that are most harmful. Without this information, policies aimed at reducing concentrations of individual pollutants globally without focusing on specific sources will continue to be inefficient and less effective than they could be in protecting the population from the adverse effects of air pollution exposure.
Crisp Terms/Key Words: environmental exposure, human mortality, environmental contamination, transportation /recreation safety, clinical research, human data, travel, urban area, epidemiology, asthma, hospital utilization, emergency care, environmental health, consumer product, air pollution
DESCRIPTION (provided by applicant)
The proposed project will develop and demonstrate a personal exposure monitor which combines a novel aerosol concentrator, a micro-particle collector, and a microfluidic sample processing and detection platform customized to perform a broad range of assays, coupled to automated data recording and/or transmitting equipment and a position-monitoring device (such as a GPS unit) to provide time- and space-resolved measurements of a wide range of environmental agents. This exposure monitor will significantly improve the ability to localize exposure events in space and time and will provide a critical tool for use in resolving uncertainties about the relationships between exposure and human health impacts.
In the proposed project we will customize our aerodynamic lens aerosol concentrator technology for use in a portable air sampler, we will integrate the aerosol concentrator with a capillary aerosol particle collector, and we will interface this particle collection system to a microfluidics card where biological or chemical assays will be carried out and the results detected. Enertechnix, Inc. will be responsible for adapting its existing aerosol concentration and collection technology and Micronics, Inc. will adapt its commercial microfluidics card technology for use in a portable exposure monitor. The University of Washington will develop specific assays that can be adapted for implementation in the microfluidics environment for detection of target biological and chemical agents.
Aerosol handling components will be developed by Enertechnix using engineering and CFD modeling capabilities previously developed for other Government-funded projects. These components will be tested using an existing, fully instrumented aerosol chamber and a variety of standard diagnostic methods for particle and bacterial detection such as epi-fluorescence microscopy, bulk fluorescence, culture, real-time PCR, etc. Microfluidic circuitry will be designed and prototyped by Micronics using methods and tools previously developed for production of similar microfluidic cards employing nucleic acid and immunological assays and electrochemical and other detection methods. Specific assays will be developed by the University of Washington using its extensive expertise and laboratory facilities in the areas of microbiology, chemistry, environmental science (atmospheric pollutant detection and characterization), etc.
DESCRIPTION (provided by applicant): The average person in the U.S. contains detectable levels of more than 100 industrial compounds, pollutants, and chemicals, but predicting the relative risk of this exposure, especially over time, is challenging (US CDC, 2003). Successful development and commercialization of next-generation, low-cost, high-performance technology for predicting compound toxicity would help assess safe levels of environmental exposure-thereby reducing national healthcare costs and producing safer working/living environments. This exposure to environmental toxins plays an important role in aging and oxidation processes, which are key risk factors of macular degeneration, a process that eventually leads to blindness. Importantly, however, there are currently no accepted or practical tests for measuring the retinal toxicity of compounds directly. In vivo assessments of retinal toxicity, when performed, require large numbers of animals, are time-consuming and expensive, and do not provide data on toxicity progression. The ability to prepare stable primary mixed retinal cultures in vitro would allow screening and prioritization of further toxicity testing in a rapid and cost-effective manner. Ideally, such a system should allow differentiation of light-dependent toxicity [phototoxicity] and general toxic effects, and would mimic in vivo toxicity. Therefore, the overall goal of this multi-phase SBIR project is to develop, validate, and commercialize Ocuscreen(tm), Acucela's proprietary retinal culture screening system, as a next-generation in vitro system for ranking the relative (photo)toxicity of environmental toxins, and to have this assay incorporated as a part of the regulatory framework for the commercialization of chemicals. The Specific Aims for Phase I of this project are to identify a group of known retinal toxicants, to prove the feasibility of ranking their (photo)toxic potential, and finally to show these rankings correlate with in vivo literature data. Demonstrating that we can predict (photo)toxicity (or lack thereof) in a small class of representative compounds will establish the predictive potential of our new system within the limited scope of the Phase I proof-of-concept project, and will set the stage for a larger Phase II demonstration effort. Phase I will also provide sufficient data for Ocuscreen to be nominated as an alternative test method to the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and will allow us to determine how well Ocuscreen meets ICCVAM performance standards. Phase II work will involve establishing a large photoreceptor toxicity database of chemicals-built both from existing knowledge and results from our assay system-to improve the predictive accuracy of compound safety. Phase III of the project will be focused on establishing a commercial screening service for photoreceptor toxicity. Even without formal regulatory adoption, the ability to accurately predict toxic potential will provide a compelling service to chemical companies and will represent an important step in protecting human health. The average person in the U.S. contains detectable levels of more than 100 industrial compounds, pollutants, and chemicals, but predicting the risk of this exposure, especially to eye toxicity, is challenging. Current prediction methods require large numbers of animals, are time-consuming and expensive, and do not provide data on toxicity progression. The overall goal of this project is to develop, validate, and commercialize Acucela's proprietary retinal culture screening system as a next-generation, practical in vitro system for evaluating the health effects of environmental toxicants.
DESCRIPTION (provided by applicant)
The goal of this proposed midcareer investigator award is to expand training in multi-disciplinary research focused on the environmental health sciences at the University of Washington. Through collaborations with several ongoing training programs, the candidate, Joel D. Kaufman, MD, MPH, will expand current research efforts and develop a mentoring program with trainees from several relevant disciplines. This program will integrate experimental, epidemiologic, and translational approaches to the role of environmental factors in cardiovascular disease.
The proposed research is a continuation of two thematically related projects from Dr. Kaufman's ongoing research program. Both address the thesis that particulate matter air pollution exerts its effect through systemic oxidative stress and inflammation, which in turn results in endothelial dysfunction. The first project studies the effect of diesel exhaust particulate on endothelial function in controlled inhalational exposures, addressing mechanistic hypotheses to understand the role of systemic oxidative stress. The second project is based in an epidemiological study of air pollution effects on cardiovascular disease, and examines the joint and independent effects of acute and chronic pollution exposures on plasma markers of endothelial activation, oxidative stress, and systemic inflammation in a multi-ethnic population-based cohort.
The mentorship program builds on Dr. Kaufman's success in multi-disciplinary research, and aims to provide research mentorship in patient-oriented environmental health sciences research to trainees from a wide variety of disciplines. These will include fellows in occupational and environmental medicine, pulmonary medicine, allergy, and cardiology; medical students; and graduate students in epidemiology, toxicology, occupational and environmental hygiene, and environmental engineering. The program will include a research infrastructure (research assistance, data analysis, and biostatistics) and supervised research mentorship. The University of Washington provides an outstanding setting for collaborative training and patient-oriented research in environmental health sciences.
DESCRIPTION (provided by applicant)
The investigators are applying for support for years 31 to 35 for the Environmental Pathology/ Toxicology (EP/T) Program at the University of Washington (UW), a Training Program that has been continuously been funded by the NIEHS since 1978. The long-term goal of the investigators' program remains mentoring pre- and postdoctoral trainees to become successful independent scientists who are well equipped to respond to the environmental health research needs of the US in the coming generations. The long-established program has been highly successful in this endeavor, and proposed changes ensure that it conforms closely to the NIEHS Strategic Plan 2006. The investigators also are highly responsive to the recent restructuring of T32 applications announced by the NIEHS (NOTES-06-007). The Program is a 30-year-long collaboration between the Department of Pathology (School of Medicine) and the Department of Environmental and Occupational Health Sciences (DEOHS; School of Public Health and Community Medicine). The EP/T Program is divided into four research core areas (leaders): Gastrointestinal, Liver, and Kidney (Dr. Eaton); Neurotoxicology and Reproductive Biology/Development (Dr. Costa); Cardiorespiratory (Dr. Kavanagh); and Molecular Mutagenesis and Carcinogenesis (Dr. Monnat) with 27 training faculty, an increase of 5 from the previous cycle, who are mostly from the DEOHS (11) or the Department of Pathology (10). New to this competitive renewal is the addition of pre- and post-graduate training as well as three faculty in Genome Sciences, and new opportunities for trainees to participate in translational and clinical research programs. The EP/T Program is directed by Dr. Thomas Montine (Program Director), Dr. Elaine Faustman (Deputy Director), and a Steering Committee constituted by the research core leaders. The Program includes virtually all NIEHS-supported investigators at UW, is closely linked with NIEHS-supported centers at UW focused on ecogenetics, toxicogenomics, and risk assessment, among others, and is highly integrated with a wide array of well-funded, complementary research centers and projects. Given the investigators' excellent track record of training as well as the outstanding and growing opportunities at UW, they propose to increase their Program with two additional postdoctoral training positions for a total of 8 pre-doctoral and 5 postdoctoral trainees, and thereby continue to train future leaders in environmental heath science.
BACKGROUND
The current application proposes an increase of 2 postdoctoral positions for a total of 8 pre-doctoral and 5 postdoctoral positions. The faculty will be increased to 27, an increase of 5 mentors since the previous grant application. Basic research on disease mechanisms related to environmental health was the initial scope of the program when initiated in 1978 and was expanded to include research Clusters (cores) in 1998 (Cluster 1: Gastrointestinal, Liver and Kidney; Cluster II: Neurologic, Reproductive, and Developmental; Cluster III: Cardiorespiratory Diseases; and Cluster IV: Molecular Mutagenesis & Carcinogenesis. In the upcoming application period these aspects will be maintained and added emphasis will be placed on genome sciences and new opportunities for training and participation in translational and clinical research. The added emphasis on genome sciences for pre-doctoral and postdoctoral students is also reflective of the integration of the University of Washington's Genome Sciences Graduate Program into the proposed Training Program.
DESCRIPTION (provided by applicant)
The Department of Environmental and Occupational Health Sciences in the University of Washington, School of Public Health and Community Medicine proposes to establish a summer research training experience for undergraduate science students under the NIEHS STEER initiative. The intent of this program will be to emphasize undergraduate research experiences and instruction plus interactive learning in related topics preparatory to entering graduate programs in environmental health sciences. The investigators intend to pursue the twin goals of bringing the opportunity to experience high quality environmental health research activities to students of outstanding potential, and to actively recruit highly qualified students from disadvantaged or under-represented groups.
DESCRIPTION (provided by applicant): The primary purpose of this pilot project is to test the feasibility of using Spanish language radio dramas (radio novelas) with call-in follow-up as a way to enhance community understanding and open a dialog about biomedical and behavioral research directly pertinent to the health of the Hispanic community in the Yakima Valley of Washington. The project will use community based participatory methods to select topics and will tap into the broad expertise of researchers within the University of Washington. Radio novelas will introduce and dramatize selected health topics within an imaginary Hispanic family (the Romeros) and follow-up radio call-in sessions will provide an opportunity for dialog between researchers and the community on the topic. The radio novelas will present an entertaining lay discussion of the health topic, the research issues and the value of scientific inquiry about the topic. They will serve to educate and engage the community. The follow-up call-in program will provide an opportunity for community members to ask questions and make suggestions to an active researcher with expertise in the field and to educate researchers about concerns of the community. Several approaches to evaluation are described. The University of Washington will partner with Northwest Communities Education Center/Radio KDNA, the Yakima Valley Farm Workers Clinic and Heritage University in this community-based participatory research project. These organizations have worked collaboratively over the past four years in a community-university partnership called "El Proyecto Bienestar/ The Well-Being Project". Evaluation data will support the development of new research proposals and expansion of the method if proven effective. The transferable products of this project will be a series of radio novelas available to other radio stations. Also, if successful, a demonstration of a tool for enhanced communication between researchers and the Hispanic community of the Yakima Valley and the validation of an important communication mechanism for future use by El Proyecto Bienestar.
DESCRIPTION (provided by applicant)
Childhood obesity rates continue to increase in the U.S. and internationally, particularly among youth in middle childhood and adolescence, with alarming anticipated health consequences. Such increasing prevalence of obesity requires a systematic evaluation of the factors contributing to this epidemic, particularly environmental factors that are amenable to policy change. Recent empirical evidence, paired with emerging concepts that integrate urban planning and public health, suggests that adult obesity and weight-related behaviors are related to neighborhood built environment characteristics. Very few studies have evaluated the association between built environmental and child weight status or change in child weight status. The present study aims to 1) evaluate the association of neighborhood-level physical activity and nutrition environment with children's weight status after controlling for known individual and familial risk factors, and 2) evaluate the ability of neighborhood-level environmental factors to predict the change in children's weight status over a 2-year period. This will be a multi-level observational study. Census block groups in two distinct regions in the U.S. (Cincinnati, OH & San Diego, CA) will be screened, clustered to form neighborhoods, and selected for study based on the built environment constructs of walkability (combination of street connectivity, residential density, land use mix, and retail floor area ratio), public recreation space quality, and nutrition environment quality. Walkability indices will be created through existing parcel-level and street network information in these regions. Public recreation space and nutrition environment quality indices will be created using established psychometrically sound direct observation instruments. Forty neighborhoods (n=20 per region) with socioeconomic diversity will be selected for study based on these built environment constructs, with additional environmental variables also collected (e.g., crime). Twenty children 6-10 years old and a parent will be randomly selected from each of the study neighborhoods (n=800 total pairs). Child weight status, physical activity, and dietary intake will be directly assessed at baseline and 2 years following baseline. Home and school environment factors related to their child's weight status will be reported by parents, and parental weight status, early child feeding experiences, and demographics will be obtained. The proposed trans-disciplinary project team combines expertise in studying obesity, physical activity, nutrition, and their relation to built environment factors. The proposed study addresses critical unanswered questions regarding associations of neighborhood built environment with childhood obesity and related behaviors. The proposed detailed evaluations of multiple dimensions of the built environment and use of best-available measures will advance science and provide information that can be used by policymakers to contribute to controlling the epidemic of childhood obesity.
DESCRIPTION (provided by applicant)
Recent advances in nanotechnology have produced a new class of fluorescent nanoparticles, semiconductor quantum dots (QDs). These nanometer-sized crystals have unique photochemical and photophysical properties that are not available from either isolated molecules or bulk solids, and consequently have enabled new opportunities in many areas including optoelectronics, anti-counterfeiting inks, and photovoltaics. More recently, the research interest in QDs has shifted toward the life sciences, where material scientists, chemists and biologists are working together to develop these quantum-confined nanocrystals as fluorescent probes for biomedical imaging. Compared with organic dyes and fluorescent proteins, semiconductor QDs offer several unique advantages, such as size- and composition-tunable emission from visible to infrared wavelengths, large absorption coefficients across a wide spectral range, and very high levels of brightness and photostability. High-quality QDs are generally made from group II-VI and -V elements in the chemical periodic table including Cd and Hg, which are toxic heavy metals. Our preliminary results indicate that polymer-protected QDs remain intact in live cells and animals for up to 2-4 months and are non-toxic. But their long term degradation, metabolism, and clearance are still unknown, which will ultimately determine the suitability of QDs for biomedical applications. Furthermore, because QDs intended for applications other than biomedicine will not necessarily be designed with biocompatibility in mind, concerns have been raised regarding potential occupational and environmental exposures to QDs. In this context, we propose to systematically investigate the toxicity of QDs of different chemical compositions. We will focus on QDs that have practical applications in photonics, optics, solar cells, sensors and biomedical imaging. We hypothesize that the colloidal stability and nanomaterial surface properties such as surface ligands and functional groups will affect in vitro and in vivo behavior and toxicity of QDs. In order to address this hypothesis, this application will focus on innovations of nanoparticle synthesis and surface engineering, in vitro toxicity to multiple murine and human cell types, and in vivo toxicity in genetically modified mice. Information gathered from these studies will be valuable in helping to predict the role of various constituent metals on the toxicity of QDs, as well as in the design of cores and coatings that will optimize the desirable properties of these materials while minimizing their adverse health impacts. Such information will be useful in risk assessments of these materials, and thus help to inform regulatory policy making.
DESCRIPTION (provided by applicant): Exposure to toxic metals like cadmium (Cd), lead (Pb), mercury (Hg), chromate (CrO42-), arsenite (As) (III), and arsenate (AsO43-) are known to induce various diseases that are detrimental to human health. One of NIEHS emphasis areas is the development of "Chelation chemistry that can serve as the foundation for therapies to ameliorate aberrant metal accumulations and the effects of toxic exposures." In response to PA-06-181, this Exploratory/Developmental R21 proposal will develop and evaluate novel biocompatible chelating materials that will lead to a breakthrough in the field of chelation chemistry, specifically for heavy metals in humans after environmental exposure. This work addresses a key mission of NIEHS since the institute "has primary responsibility with respect to toxic metal exposure from environmental sources." Complete chelation therapies encompass (1) chelating the metal ions in the gastrointestinal fluids in order to limit systemic absorption of ingested materials and (2) chelating the metal ions in blood that have been absorbed systemically from all routes of exposure (oral, dermal and inhalation). Since the 1940s, in vivo toxic metal immobilization has involved the use of ethylenediamine-tetraacetate (EDTA) or dimercaptosuccinic acid (DMSA) following metal exposures. However, these chelation agents still have many disadvantages and low efficacy. They are also not effective in removing Cd and toxic anions such as chromate and arsenate. We hypothesize that functionalized silica (SAMMS) and magnetic nanoparticles, both proven in our numerous preliminary data and publications to be highly efficient and stable sorbents for removal of toxic metals in environmental cleanups, can also be used effectively in biological matrices for metal decorporation in humans. They will be better than the currently FDA-approved EDTA and DMSA in terms of higher affinity, specificity and capacity. In addition, we hypothesize that these new chelating materials will exhibit a faster removal rate, less toxicity, and overall their use will result in lower costs of treatment. To test the hypothesis, SAMMS will be evaluated for toxic metal removal from gastrointestinal (GI) tract while magnetic nanoparticles will be evaluated for extracorporeal chelation of toxic metals from whole blood. Differing organic groups will be carefully designed to have a high affinity for the target metals. Assessment of chelating performance, material stability, protein fouling, and cell uptake of the nanomaterials will be done in vitro using relevant physicochemical forms and concentrations of the metals appropriate to acute and chronic human exposure of the toxic metals. Refinement of both materials to increase their stability as well as minimize protein fouling and cell uptake will also be performed. The results will form a strong foundation for our continued effort with in vivo studies using animal models in a future R01 project. Exposure to toxic metals like cadmium (Cd), lead (Pb), mercury (Hg), chromate (CrO42-), arsenite (As(III)), and arsenate (AsO43-) are known to induce various diseases that are detrimental to human health. One of NIEHS emphasis areas is the development of "Chelation chemistry that can serve as the foundation for therapies to ameliorate aberrant metal accumulations and the effects of toxic exposures." In response to PA-06-181, this exploratory R21 proposal will develop and evaluate novel biocompatible nanomaterials that will lead to a breakthrough in the field of chelation therapies of the above heavy metals by substantially outperforming the current FDA-approved chelating agents.
DESCRIPTION (provided by applicant)
We propose a quantitative structure activity relationship (QSAR) approach to investigate the specific physical and chemical surface properties that influence nanoparticle biocompatibility. Amorphous silica is chosen as an experimental particle due to its widespread use in consumer products, and because it is readily synthesized in a wide range of defined sizes and surface chemistries. Our recent work shows that the bioactivity of amorphous silica is greatly enhanced in particles <50 nm. We hypothesize that this is due to changes in the silanol site surface chemistry as particle diameter is decreased.
Our approach involves three aims: 1) A panel of nanoparticle-induced secreted proteins will be identified using advanced mass spectrometry-based proteomic analysis of conditioned medium from macrophages exposed to amorphous silica, coupled with our existing gene microarray data. Bioinformatic pathway analysis will be performed to select ~20 pathway biomarkers, which will be used to modify an antibody sandwich-based protein ELISA microarray platform for multiplexed response analyses. 2) A series of silicabased particles where size and surface chemistry is selectively altered with functional groups will be prepared and characterized for size, charge, aggregation state, dissolution products and silanol types. X-ray absorption near-edge spectroscopy will be used to identify surface silicon isoforms in particles adsorbed to micelles mimicking cell membranes. The biological responses of each particle will be assessed in multiwell cellular assays with macrophages, using the ELISA microarray platform to provide quantitative measures of dose-response for ~20 different pathway markers. QSAR analyses will be performed with the measured physicochemical parameters and biological response data to identify relationships that correlate most strongly. 3) Particles selected from QSAR analysis will be further tested in mice exposed by intratracheal instillation, and biological responses will be determined by histopathology along with ELISA microarray analysis of bronchial lavage fluid. Comparison of QSAR results obtained in aims 2 and 3 will determine how predictive the in vitro assay is, as well as highlight particle characteristics that are most important for dictating biocompatibility in vivo. The results will determine properties of nano-scale amorphous silica that determine its biocompatibility, and reveal general principals relevant to other types of nanomaterial. In addition, the approach and biomarkers developed from this work will provide a screening platform that can be deployed to a variety of nanomaterials in the future.
DESCRIPTION (provided by applicant): The major objective of the proposed research is to understand the structural basis for the functional differences observed in human paraoxonase (PON1) genetic variants. We have partially characterized the effects of five coding region polymorphisms and five upstream regulatory polymorphisms. The Q192R polymorphism affects the catalytic efficiency of PON1 for hydrolysis of a number of substrates, while the position -108C/T polymorphism affects PON1 expression. Three newly discovered polymorphisms result in inactive PON1 alleles. Our goal is to understand the functional genomics of these polymorphisms. We will use a PON1 mouse model to examine the effects of acute exposure to organophosphorus (OP) compounds. The mouse model includes PON1 knockout mice as well as knockout mice expressing one or more copies of each human PON1-Q192R allele. This model system will allow us to test the hypothesis that a polymorphic PON1-Q192R allele expressed at a given level will provide a specific degree of resistance to the toxicity of environmental agents hydrolyzed directly by PON1 or metabolized through the cytochrome P450 /PON1 pathway. The model will also allow us to investigate the effects of PON1 polymorphisms in modulating the effects of low level OP exposure on gene expression in the brain, an area of research that has not been previously approachable. We propose to investigate five facets of PON1 genetic variability that will provide information on the functional genomics of the polymorphisms of the human PON1 gene. Specific aim 1 examines the toxicological effects of acute exposures of diazoxon (DZO), chlorpyrifos oxon (CPO) and chlorpyrifos (CPS) on mice whose PON1 genes have been replaced with one or two copies of human PON1 Q192 or R192.Specific aim 2 examines the modulating effects of the PON192 variants on the toxicogenomic expression profile of genes in the affected subregions/cells of brains of PON1-192 transgenic mice exposed to CPO and DZO. Specific aim 3 is aimed at identifying new protein targets modified by exposure to CPO. Specific aim 4 involves determination of the crystal structure of human PON1 and characterization of recombinant PON1 variants with increased efficiency of OP hydrolysis. Specific aim 5 involves development of a human pharmacokinetic/pharmacodynamic (PDPK/PD) model of organophosphate exposure using humanized transgenic PON1 knockout mice expressing varying levels of each human PON1-192 isoform.
DESCRIPTION (provided by applicant)
The function of the Administrative Core is to facilitate the overall organizational structure and administrative activities of the Center, interface with NIH/NIEHS staff, foster cooperation between Research Projects and Cores, encourage criticism and advice from the program's scientists, promote fiscal responsibility, and provide a flexible administrative structure to assure the continued excellence of the overall Center and its ability to meet milestones. The management of this U54 Center, provided by the Administrative Core, includes the Center Director, two Associate Directors with experience at managing interdisciplinary research programs in academia, industry and national laboratory; a lead statisticians experienced with transcriptomics and proteomics analysis; an Internal Steering Team made up of the Director, Associate Directors, additional Research Project and Core Leaders and two pre-eminent scientific advisors. Each Research Project and Core consists of staff with the expertise to accomplish all of the milestones set forth in this U54 application with the respective leaders responsible for the experimental design, planning and implementation in coordination with the Internal Steering Team. The Administrative Core will also provide statistical support for all Research Projects and Cores to assist in data analysis, sensor platform testing and validation. In addition, the Administrative Core will assume responsibility for (a) planning and coordination of research activities within the U54 Center, (b) promote cross-disciplinary and cross- organizational interactions, (c) coordinate statistical analyses of experimental data, (d) ensure effective liaison with the NIEHS and Exposure Biology research projects, (d) ensure effective fiscal and resources management and planning, (e) preparing programmatic center documents and reports, and provide travel and conferencing arrangements, and (g) facilitate technology transfer planning.
DESCRIPTION (provided by applicant): Direct lung injury, with pulmonary complications, accounted for most of the deaths following toxic chemical exposure in the Iran-Iraq- war, the accidental release of methyl isocyanate in Bhopal, India, the Tokyo subway sarin attack, and the hostage crisis in Moscow. These tragedies exemplify how susceptible human airways are to the effects of airborne chemicals and imply that respiratory management is most important and critical for saving life. Previous reports indicate that chemical injury is associated with direct chemical reaction followed by acute respiratory distress syndrome and late complications. A large number of civilians and an increasing number of children with pre-existing medical conditions such as asthma are more vulnerable to chemical threat agents. We propose to investigate the respiratory toxicity and lung injury following inhalation exposure to the deadly chemical threat agent sarin in animal models. Our recently developed micro-instillation technology of inhalation exposure will be used for sarin vapor exposure. Micro-instillation technology bypasses the detoxification of chemical threat agents in the airway of rodents, which have high levels of carboxylesterase and mucus. Thus, the chemical agents reach alveoli and mimics an exposure similar to human. The respiratory toxicity will be assessed by toxicological, biochemical, histopathological and respiratory functional analysis. The chronology of lung injury will be also assessed. We ill identify bronchoalveolar lavage, blood biomarkers or non-invasive respiratory parameters to diagnose the severity of exposure. A number of FDA-approved or in clinical trial as well as new therapeutic regimens will be evaluated to develop an effective medical countermeasure against pulmonary injury and its long-term consequences. We will also assess the respiratory toxicity of sarin in animals models of pre-existing medical conditions such as asthma. Potential therapeutics will be evaluated for protection against sarin exposure in asthma model. The proposed studies will define the biochemical mechanisms of respiratory toxicity and lung injury that play a central role in chemical threat agent induced toxicity and a major cause of death following exposure in normal and vulnerable populations with pre-existing medical conditions. Effective therapeutics to protect against pulmonary toxicity and its long-term consequences that can complement the existing modalities will be rapidly developed for a mass scenario.
DESCRIPTION (provided by applicant)
The overall objective of this DISCOVER Center is to investigate the mechanisms by which traffic-related air pollution causes myocardial infarction and other cardiovascular diseases, by integrating a diverse set of research approaches. Air pollution exposures have been consistently associated with cardiovascular disease. A growing literature indicates that the major source of variation in air pollution's cardiovascular health effects is from exposure to traffic. Diesel exhaust is an excellent model exposure. The closely linked suite of activities in this DISCOVER Center will attempt to understand the mechanisms (molecular mechanisms that cause vasoconstriction and acceleration of atherosclerosis) underlying exposure-related effects, and use environmental exposures to understand basic mechanisms regarding vascular biology. The studies will exploit exposure contrasts in experimental and epidemiological studies through advanced exposure assessment methods, and genetic diversity in both human and animal studies, to advance our aims. The application brings together a cohesive group of five projects (two patient-oriented and three basic mechanistic studies) and three cores, Administrative, Exposure Science, and Biostatistics and Bioinformatics. Project 1 investigates the mechanism underlying vascular response in humans following controlled exposure to diesel exhaust; Project 2 studies genetic modifiers on the effect of traffic-related air pollution on vascular response and atherosclerosis in a population-based human observational study. Project 3 investigates the role of systemic inflammation in the vascular response to diesel exhaust. Project 4 investigates the impact of diesel exhaust exposure on myocardial injury and apoptosis. Project 5 investigates reactive oxygen species and oxidative stress in the vascular response to diesel exhaust. Through this research, the investigators will develop knowledge that can be used to develop preventive and therapeutic strategies.
INTEGRATED (clinical and basic) and INTERDISCIPLINARY NATURE OF PROGRAM
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