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Record Count: 27
To sort columns alphabetically or numerically, click on the column
header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant): Our long-term goal is to understand the molecular mechanisms that govern the cellular stress response, thereby exploring the potential of targeting the cellular stress signaling circuitry for prevention and treatment of human diseases. In this proposal, we will study the integration of the stress signaling network; i.e. "wiring the stress signaling circuitry", using the regulation of UV signaling by the crosstalk between NF-kappaB and JNK1 as a model system.
Using both genetic and biochemical approaches, we recently found that the transcription factor NF-kappaB, which is known as a key survival factor in cells, surprisingly functions as a pro-death factor in UV-induced apoptosis by promoting activation of c-Jun N-terminal protein kinase 1 (JNK1). Specifically, RelA/p65, which is a major transactivating subunit of the NF-kappaB family, in its pre-existing nuclear form controls expression of protein kinase c delta (PKCdelta) in non-stimulated cells. This "priming" effect allows UV to quickly activate PKCdelta, which is required for rapid and robust activation of JNK1 and cell death. We hypothesize that the novel crosstalk between NF-kappaB and JNK1 is critical in "wiring" the UV signaling circuitry in programmed cell death and tumorigenesis.
This proposal is novel, as it will determine the molecular mechanism by which the NF-kappaB-PKCdelta axis regulates UV-induced JNK1 activation and cell death, to elucidate the molecular mechanism by which PKCdelta participates in the integration of the UV signaling circuitry, and to determine the pathophysiological relevance of the novel crosstalk between NF-kappaB and JNK1 in response to physical stress in vivo.
This study will put forward a novel paradigm regarding the molecular mechanism by which the UV signaling circuitry is integrated and will also provide the rationale in developing novel strategies for prevention and treatment of physical stress-related human diseases and cancer. PUBLIC HEALTH RELEVANCE: Ultraviolet (UV) is a major physical stress and is also a complete carcinogen in skin cancer. This research is designed to determine how the information of UV-irradiation is "wired" by the crosstalk between two major cell signaling regulators, NF-:B and JNK1 in physiological and/or pathological events such as programmed cell death apoptosis and tumorigenesis. This study will test a novel paradigm regarding the molecular mechanism by which the UV signaling circuitry is integrated and will also provide the rationale in developing novel strategies for prevention and treatment of physical stress-related human diseases and cancer.
DESCRIPTION (provided by applicant): Developmental exposure to natural or environmental estrogens predisposes to prostate carcinogenesis with aging; however, the molecular underpinnings of this phenomenon are unclear. We present evidence that developmental reprogramming of the prostate by estrogens may be mediated, in part, through epigenetic alterations. Using methylation-sensitive fingerprinting (MSRP) as an initial screen for genome-wide methylation changes, we identified multiple prostatic genes whose methylation status was permanently altered in rats as a result of neonatal estradiol and bisphenol A (BPA) exposures at environmentally relevant doses. Detailed characterization of phosphodiesterase 4D4 (PDE4D4) and HPCAL, enzymes involved in cAMP breakdown and formation, respectively, revealed aberrant promoter CpG island methylation patterns with resultant changes in gene transcription as the animals aged. Importantly, these epigenetic alterations were associated with increased susceptibility to hormonal carcinogenesis of the rat prostate gland. Thus we hypothesize that early estrogenic imprinting of the prostate gland with resultant predisposition to carcinogenesis with aging is mediated through epigenetic modifications which permanently affect gene expression in the gland. The objectives of the present proposal are to further characterize our model of developmental reprogramming by low dose estradiol or BPA, to characterize in detail the prostatic gene methylation and transcriptional alterations which result from early life estrogenic exposures and to identify the methylation candidate genes contribute to increased carcinogenic potential in the developmentally estrogenized prostate glands. In Aim 1, we will determine the dose-response relationship for prostatic- BPA effects and establish the developmental windows of susceptibility. We will also use a novel tissue recombination model to test whether BPA modifies carcinogenic susceptibility and methylation patterns in human prostate-like structures. In Aim 2, we will characterize in detail the altered rat prostate methylome with resultant alterations in gene expression as a result of developmental exposures to environmentally relevant doses of BPA or estradiol. MSRP and methylation arrays will be used to expand our prostatic screen to identify a full panel of candidate genes and a stringent algorithm will be followed to identify candidates with regulatory CpG islands. Site-specific methylation and resultant transcriptional regulation will be confirmed. In Aim 3, we will directly test whether the genes epigenetically modified by estrogenic exposures play an active role in prostate gland carcinogenesis using a variety of in vitro and in vivo studies.
The specific aims of the Center for Interdisciplinary Health Disparities Research are to: Aim #1: bring together scientists from inside and outside the University and members of the community who are especially vulnerable to adverse health conditions to inform the Center's scientific agenda; Aim #2: foster investigations that consider health disparities from multiple levels of analysis via shared conceptual frameworks that integrate discipline-specific theories and methods; Aim #3: increase interest in health disparities among scientist and students from various disciplines and from community members; Aim #4: develop measures and methods that are appropriate for use with vulnerable populations and that allow factors at various levels (social/environmental, behavioral/psychological, and biological/genetic) to be
analyzed together; Aim #5: increase existing knowledge on the social, behavioral, and biological factors that influence health disparities and the nature of their interactions; and, Aim #6: disseminate findings through channels established through the Center to as wide an audience as possible, including members of vulnerable populations, community-based organizations and agencies, and scientific investigators inside and outside the University.
In its first five years, the Center will focus on group differences in breast cancer, notably why Black women in the US and West Africa experience breast cancers that occur at a younger age and are more aggressive and lethal than those of White women. McClintock (R01 # 1), based on an animal model of social regulation of mammary tumor biology developed in her laboratory, will compare the gene regulation in mammary tumors and the ovarian function of socially isolated and group-living rats. OIopade (R01# 2) will (a) look at the molecular characterization of primary patient samples in Nigeria and Chicago's South Side to see if alterations in BRCA1 contribute to breast cancer in younger Black women and (b) explore the McClintock model in primary patient samples. Gehlert and Masi (R01# 3; CBPR) will explore emic views of breast cancer and its treatment and test the McClintock model with community volunteers. In the lalffer, they will examine neighborhood and community factors (such as collective efficacy and crime), living situations and social connectedness, behavioral responses (such as vigilance and perceived stress), and biological (e.g., cortisol levels) and health outcomes (most notably breast cancer). Conzen (R01# 4) will study rate of mammary tumor growth, response to chemotherapy, and chemoprevention in two animal models. The Tissue Core will provide analysis of mammary tissue. Coordination and dissemination will occur through the Administrative Core, by means of Faculty Colloquium and Monthly Speaker Series, In-Service and Summer Apprenticeship
programs, a Center Web site and Web page for communication with other CPHHDs, etc.
Crisp Terms/Key Words: breast neoplasm, clinical research, behavioral /social science research tag, health services research tag, health disparity
DESCRIPTION (provided by the applicant):
Ambient participate matter (PM) air pollution contributes significantly to cardiopulmonary morbidity and mortality. There are strong epidemiologic data that link daily levels of ambient PM to hospitalizations for cardiopulmonary disease and daily rates of cardiovascular mortality. Acute exposure to increased levels of PM is also associated with increased risk of acute myocardial infarction, and ischemic stroke. However, the mechanisms by which PM elicits these pathologic events and increases cardiovascular mortality are largely unknown. Exposure of animals and humans to PM alters hemostasis; increasing the levels of fibrinogen, and von Willebrand factor and inducing peripheral arterial thrombosis. In support of a PM-induced prothrombotic state, we have recently observed that exposure of mice to well-characterized PM collected from ambient air in Dusseldorf, Germany caused shortening of the bleeding, prothrombin and partial thromboplastin times, and increased the platelet count and the levels of factor VIII. Moreover, exposure of mice to PM increased bronchoalveolar lavage fluid levels of IL-6, which promotes coagulation and enhances platelet production and thrombin formation. Accordingly, we found that generation of intravascular thrombin was increased 24 hours after exposure to PM. The effect of PM-exposure on thrombin formation was abrogated in mice with targeted deletion of IL-6. Similarly, inhibition of beta-adrenergic receptors, an important regulator of IL-6, attenuated PM-induced thrombin generation. PM-induced stimulation of inflammation and cytokine release has been suggested to be due to the generation of reactive oxygen species (ROS) by epithelial cells and macrophages. These new findings led us to hypothesize that PM causes IL-6 release, which causes a hyper-coagulable state via a ROS-dependent mechanism. To test our hypothesis, we propose to (1) determine whether PM-induced IL-6 production and the resultant hyper-coagulable state are mediated by alveolar macrophages, alveolar epithelial cells, or both, (2) determine whether the PM-induced generation of ROS is required for IL-6 production and the resultant hyper-coagulable state, and (3) determine the role of beta-adrenergic receptors in modulation of the PM-induced IL-6 production and hyper-coagulable state. The studies we are proposing address an important human health problem and could lead to the development of novel therapies to diminish PM-induced cardiovascular events and mortality.
DESCRIPTION (provided by applicant)
This application is a continuation of an epidemiologic study that investigates the effect of socio-economic disadvantage and neighborhood conditions on disability in older blacks and whites. The proposed project takes place in the context of a population-based, longitudinal study of persons aged 65 years and over who live in a geographically defined, urban, biracial community area in Chicago. During the initial funding period, the investigators have successfully collected yearly disability outcome data, and detailed information on neighborhood conditions using self-report instruments and a systematic neighborhood survey of the study area. The first overall goal of this continuation is to determine the relative contribution and specific nature of the neighborhood conditions that are associated with disability in older adults. The second overall goal is to determine the biological mechanisms through which neighborhood conditions lead to increased disability, focusing specifically on hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, via salivary cortisol, and inflammatory processes, via interleukin-6 (IL-6) and C-reactive protein (CRP), obtained from blood samples. To accomplish these goals, the investigators propose to continue yearly collection of disability outcome data and obtain blood samples and salivary cortisol from over 7,000 participants. These data will be integrated with a rich set of existing data on personal characteristics, health conditions, and neighborhood factors to test a series of specific hypotheses related to the overall goals.
Disability is a common and highly prevalent consequence of age-related chronic diseases, and a critical indicator of overall health among older people. Prevention of disability is essential to improve the lives of older people and reduce health care costs. The proposed work will contribute to a better understanding of the specific neighborhood conditions that are associated with increased disability, laying the foundation for more effective policies to prevent disability in future generations of older adults.
DESCRIPTION (provided by applicant): Cadmium (Cd2+) is an important industrial and environmental pollutant that can cause severe damage to a variety of organs including the lung, kidney, liver, and bone. In addition, Cd2+ has been shown to have teratogenic and carcinogenic activities. In spite of its importance as an environmental health problem, relatively little is known about the specific cellular and molecular mechanisms by which Cd2+ produces its adverse effects. The long-term objective of this project is to identify some of these mechanisms. Evidence from the literature suggests that some of the effects of Cd2+ in vivo may result from the disruption of the junctions between cells in various epithelial and endothelial surfaces. Results of recent studies have shown that Cd2+ can selectively disrupt the Ca2+-dependent junctions between various types of epithelial cells in culture, and that these effects most likely result from the interaction of Cd2+ with the Ca2+-dependent cell adhesion molecule, E-cadherin. More studies that are recent have shown that Cd2+ can disrupt E-cadherin- and VE-cadherin-dependent cell-cell junctions in the lung and alter the localization of E-cadherin and N-cadherin in the kidney. Additional results on cells in culture suggest that the loss of cadherin-mediated adhesion results in the translocation of the cadherin-binding protein beta-catenin from the junctional complexes to the cell nucleus and possible alterations in gene expression. These results suggest that the cadherin/beta-catenin complex may be an important early target of Cd2+ toxicity in epithelial cells of the lung and kidney. The work described in this proposal is a direct extension of these previous studies, and is aimed at resolving two major issues. The first objective is to continue ongoing studies examining the effects of Cd2+ on the cadherin/catenin complex in vivo, and to determine if this mechanism might contribute to the toxic effects of Cd2+ in specific target organs such as the lung and the kidney, which are important targets of Cd2+ toxicity in humans. The second objective is to examine the possibility that the Cd2+-induced disruption of the cadherin/beta-catenin complex may lead to the translocation of beta-catenin from the junctional complexes to the nucleus and alterations in beta-catenin-regulated gene expression. These issues will be addressed by employing a multidisciplinary approach that includes both in vitro and in vivo studies that utilize a variety of physiologic, morphologic and biochemical techniques. Results of these studies should provide important new insights into the mechanisms by which Cd2+ produces some of its toxic effects. Furthermore, the results of these studies could have more general implications regarding the mechanisms by which toxic substances affect living organisms.
The overall goal of the FRIENDS Children's Environmental Health Center is to understand the impact of
prenatal exposure to contaminants found in fish-including polychlorinated biphenyls (PCBs),
polybrominated diphenyl ethers (PBDEs) and methyl mercury (MeHg)-on cognitive, motor and auditory
function of children. The animal studies described in this proposal will complement a parallel prospective
birth cohort study (Project 2) in which children born to women consuming fish contaminated with these
chemicals will be followed longitudinally from birth. The animal studies will'use an experimental PCB mixture
that mimics the PCB congener profile in the fish consumed by women in the epidemiological study. One
major goal is to elucidate the effects of PCBs and PBDEs on important executive processes including
attention and inhibitory control. Drug challenges with methylphenidate and amphetamine will determine if
commonly prescribed ADHD pharmacotherapies improve the performance of PCB- or PBDE-exposed rats
on tests of attention and response inhibition, and measures of DA D4 and DA D1 receptor expresion and
drug challenges using specific DA D4 and DA D1 receptor agonists will indicate whether these receptor
pathways are involved in mediating the behavioral effects. These studies will be conducted in parallel with
another laboratory study (Project 4) which will investigate the effects of PCB and PBDE exposure on central
catecholamine function and the extent to which these effects are mediated indirectly through PCB or PBDE
effects on circulating thyroid hormones. A second major goal is to understand the mechanisms through
which PCBs damage the cohclea and produce hearing loss. Histological examinations of the cochlea will
confirm whether hearing deficits are due to outer hair cell damage. The contribution of reductions in
circulating thyroid hormones or alterations in ryanodine receptor expression in the cochlea to PCB-induced
hearing loss will be investigated by utilizing two specific PCB congeners having opposing effects on thyroid
hormones and ryanodine channel activity. Because the outer hair cells are believed to protect against noise
induced hearing loss, studies will also be conducted to determine if early PCB exposure increases
susceptibility to noise-induced hearing loss later in life. As in the past, findings from these animal studies will
guide the selection of outcome measures for use in the birth cohort.
DESCRIPTION (provided by investigator): The goal of this project is to identify variants in environmentally responsive genes that modulate the genetic susceptibility of individuals to amyotrophic lateral sclerosis (ALS). Considerable progress has been made in identifying genes (SOD1 and ALSIN) and loci (chromosomes 9, 15, 16, 18, 2 and x) in the familial form of ALS but the etiology of sporadic ALS (SALS) remains unknown. To address the genetic contribution to SALS we have collected a large set of trios, case-control and discordant sib-pairs resources and now have sufficient material to test specific hypothesis. To fulfill our goal we will initially use a functional candidate approach to screen genetic variants in 410 environmentally responsive genes in two cohorts of ALS patients and controls. The associations detected with ALS will be verified in a second cohort of 500 case-controls subjects. We have used bioinformatics tools to mine a fairly comprehensive list of environmentally responsive genes from several databases including those identified by the NIEHS. We will screen variants (SNP's) in these genes using a high-throughput genotyping system and examine the SALS susceptibility and phenotype for allelic association to these genes. The initial screen will employ 250 trios and 500 case controls subjects. Promising candidates will be validated using a second set of 500 cases and controls and in discordant sibpairs. Furthermore, we will examine the genes associated with SALS for gene-gene and gene-environment interactions. Identification of gene variants associated with SALS or with the SALS sub-phenotypes (e.g. Age-at-onset, site-of-onset, bulbar/spinal etc.) will allow us to test genes in the entire pathway to which the candidate gene belongs. This project will therefore allow a focused study of environmentally responsive genes using a large resource of family and singleton ALS cohorts and will generate resources to investigate new approaches to ALS pathogenesis and in formulating rational treatment. The causes of sporadic ALS are largely unknown, and rational therapy is therefore not possible. A genetic susceptibility to environmental toxicity is considered to underlie ALS. We have a large cohort of ALS patients, siblings, parents and control subjects. We will use this unique resource to analyze the association of DNA variations in genes involved in detoxification of environmental toxins to ALS, and test the identified genes for their interaction with environmental exposures. This study will open fresh ground to investigative mechanisms of disease in ALS for formulation of rational treatment.
DESCRIPTION (provided by applicant): Mammalian ovaries contain a finite number of antral follicles. These follicles are essential for female reproduction because they contain the oocytes necessary for fertilization and they synthesize and secrete the hormones required for menstrual/estrous cyclicity, maintenance of the reproductive tract, and fertility. The organochlorine pesticide methoxychlor (MXC) poses a threat to female reproduction because it is commonly used in many countries and it selectively destroys antral follicles in a variety of species by increasing their rate of atresia (e.g., death of antral follicles). To date, little is known about the mechanisms by which MXC induces atresia of antral follicles. Preliminary data indicate that MXC induces atresia by altering the levels of highly conserved regulators of apoptosis known as the Bcl-2 family of proteins. In addition, preliminary data and the literature suggest that MXC and/or its metabolites may induce atresia by increasing the formation of reactive oxygen species and reducing the levels of proteins that protect cells from oxidative injury, including superoxide dismutase (SOD), glutathione (GSH), glutathione (GSH) peroxidase, GSH reductase, and catalase. Thus, based on preliminary data and the literature, the proposed work will to test the hypothesis that MXC and/or its metabolites cause atresia of antral follicles by altering the levels of selected Bcl-2 family members (Bcl-2 and Bax) and/or reactive oxygen species and proteins that protect cells from oxidative injury (i.e., SOD, GSH, GSH peroxidase, GSH reductase, and catalase). To test this hypothesis, the following specific aims will be completed: 1) determine whether MXC induces follicular atresia via a pathway involving selected Bcl-2 family members (Bcl-2 and Bax), 2) evaluate whether MXC induces follicular atresia by causing oxidative stress in antral follicles, and 3) determine whether MXC itself or the metabolites of MXC are responsible for follicular atresia. This work will greatly improve our understanding of the mechanisms by which MXC causes follicular atresia. In turn, this improved understanding may lead to the development of novel targets for the treatment and prevention of infertility that is caused by environmental chemicals.
DESCRIPTION (provided by applicant): A large number of human placenta samples have been collected from a multi-racial cohort children health study at the Boston Medical Center and another study entitled "Family and Children of Ukraine". The work proposed here is a small project aimed at developing a laboratory procedure for the analysis of polybrominated diphenyl ethers (PBDEs) in human placental tissues. The work will include three tasks: analytical method development and validation, examination on the integrity of stored samples, and a preliminary data collection. We will explore the applicability of a matrix solid-phase dispersion (MSPD) method and compare it with the standard and conventional procedures. Analytical sensitivity enhancement will be through the optimization of the GC injection process using a programmable temperature vaporization (PTV) large volume injector. The result of this work will be needed to initiate future comprehensive studies on prenatal exposure of human to PBDEs. A laboratory procedure is to be developed in order to understand how a wide-spread environmental pollutant affects the health of human fetus before babies are born.
Crisp Terms/Key Words: high throughput technology, method development, animal tissue, glycerol, placenta, human tissue, halobiphenyl /halotriphenyl compound, analytical method
DESCRIPTION (provided by applicant): Ambient particulate matter (PM) is increasingly recognized as a significant contributor to human cardiopulmonary morbidity and mortality both in the United States and worldwide. There are strong epidemiologic data that link the daily levels of ambient PM to pulmonary symptoms, rates of infections, school absenteeism, daily use of specific medications, hospitalizations for cardiopulmonary disease, and daily cardiopulmonary mortality rates. Longer term exposure to ambient particulate matter has been associated with an increase in the prevalence of obstructive lung disease and the development of lung cancer. While relatively little is known about the mechanisms by which particulate matter induces disease, it is hypothesized that exposure of epithelial lining cells to ambient particulate matter within the respiratory tract results in the development of reactive oxygen species (ROS) that in turn induce injury and inflammation. We have observed that exposure to well-characterized particulate matter collected from ambient air in Dusseldorf, Germany and Washington, D.C. results in death of alveolar epithelial cells through a mechanism that appears to require iron and the mitochondrial generation of ROS. In this proposal we seek to determine the mechanisms that underlie the generation of reactive oxygen species in response to exposure to particulate matter and the signaling pathways evoked that link the generation of ROS to alveolar epithelial cell death. Specifically, we seek to determine (1) whether iron and ROS generated from the mitochondria are required for particulate matter induced lung epithelial cell death in vitro and in vivo; (2) whether iron and ROS generated in response to particulate matter cause an apoptosis signal-regulating kinase 1 (ASK1) dependent activation of JNK and p38 to induce lung epithelial cell death and (3) whether the activation of p53 acts through the pro-apoptotic Bcl-2 protein PUMA to induce lung epithelial cell death following exposure to particulate matter. These studies combine molecular-genetic approaches to examine the mechanisms of particulate matter induced cell death in vitro and in vivo. Recent estimates suggest that the average loss of life expectancy related to chronic air pollution exposure is between 1.8 and 3.1 years for individuals living in the most polluted American cities. Understanding the mechanisms by which particulate matter induces injury in the lung will help us better design pollution control and response measures that will have a major impact on public health.
DESCRIPTION (provided by applicant):
The purpose of this project is to extend the investigators' previously funded
Peer Education in Pregnancy Study. The overall goal of the study is to
examine the effect of peer education aimed at modification of the home
environment on the development of asthma in children at risk for the disease.
Secondary goals are to examine the effect of environmental, psychosocial, and
nutritional risk factors on the development of asthma in the overall cohort.
Specific aims of this proposal are to increase the total recruitment to 500
pregnant women and their unborn infants; increase the time of follow-up of the
children to age 3-5 years; expand the exposure assessment to include dust
measurements of endotoxins, pyrethroids, and organophosphates and urine
measurements of pesticide metabolites; extend the psychosocial and nutritional
assessments to include measurements of family function stress and diet during
years 1-5; and expand immune assessments to include measurements of
interleukins (IL-4, IL-13, and interferon-gamma) at one year of age. The
effect of peer education on the development of asthma by age 3-5, as well as
the effect of peer education on intermediary endpoints such as smoking,
exposure to indoor allergens (cat, cockroach, mite, mouse, beta-glucan, and
endotoxins), exposure to pesticides (pyrethroids and organophosphates), and
immune function (IgE levels, skin testing for allergens, and cytokines) will
be examined. Relationships of exposure to passive smoke, allergens, and
pesticides, as well as measures of psychosocial function and nutrition, with
the development of asthma and respiratory symptoms in the overall cohort will
also be explored. Results of this study will assist in elucidating the
etiologic pathway by which asthma develops early in life, as well as assist in
the development of effective intervention programs.
DESCRIPTION (provided by applicant):
The investigators have invented a very simple, but extremely powerful, new technology for detection and identification of volatile organic compounds (VOCs): colorimetric sensor arrays. These are inexpensive, disposable sensor arrays based on equilibrium interactions of analytes with metalloporphyrins and other chemically responsive dyes. As with human olfaction, our colorimetric sensor arrays use a large number of cross-reactive sensors that probe a wide range of chemical properties. By digitally monitoring the change in color of each dye in the array, they have a quantitative measure of a composite response to volatile organics. Chemometric pattern recognition is extremely powerful with these arrays because of their very high dimensionality. the investigators are now extending this work to biomedical applications, with specific aims focusing on the development of a personal chemical dosimeter for the detection, identification, and quantification of environmental/workplace VOCs. The sensitivity of the arrays permits rapid detection of very low levels of most volatile toxicants. This is a translational technology that should find substantial use in workplace monitoring of chemical exposure. Their efforts in these areas should lead (1) to fundamental advances in sensor development for molecular recognition and biomedical applications of such sensor arrays, (2) development and refinement of technology for the rapid and continuous identification and quantitation of volatile chemical toxicants, and most importantly, (3) prototyping of an extremely portable device for the assessment of personal VOC exposure; this device will provide continuous, quantitative, reliable, reproducible, multiplexed measurement of environmental exposures with rapid response (i.e., seconds) that requires essentially no user intervention for field deployment and data capture. This self-contained, easy-to-use device will prove ideal for multi-analyte measurement of point-of-contact exposures to priority environmental chemicals for use within future population-based biomedical studies of diverse populations. The device will be able to measure analyte concentrations continuously, will require essentially no user intervention for field deployment and data capture, and will be capable of real-time telemetry to a centralized system.
DESCRIPTION (provided by applicant): DNAzymes, or deoxyribozymes are DNA molecules with enzymatic activities. Since its discovery in 1994, DNAzymes have been shown to be metalloenzymes and can be converted into metal ion sensors. Scientifically, whereas a great deal of knowledge has been accumulated in the roles of metal ions in proteins, much less is known in nucleic acids. Technologically, while enormous progress has been made in the designing sensors for diamagnetic metal ions, designing sensors for paramagnetic metal ions, particularly different oxidation states of the same metal ions remains challenging. The project seeks to fill both gaps by advancing scientific knowledge of metal-binding sites in DNAzymes, and expanding their technological applications as paramagnetic metal ion sensors that will be used to improve environmental health. Specifically we first plan to employ in vitro selection to obtain DNAzymes with high activity toward phosphodiester transfer and with strong affinity for different paramagnetic metal ions (Co2+, Cu2+ or Fe2+), or different oxidation states of the same metal ion (Fe2+ vs. Fe3+). Biochemical studies of the selected DNAzymes will provide information about conserved sequence, catalytic parameters, and pH and metal ion dependence of the enzyme activity. Biophysical characterization using UV-vis, EPR, MCD, XAS, FRET, and X-ray crystallography will elucidate affinity, stoichiometry, geometry,and ligand donor sets of the metal-binding sites in these DNAzymes, as well as reaction intermediates and mechanism. The knowledge acquired in this process will be used to convert these DNAzymes into sensitive and selective metal sensors using a patented catalytic beacon technology. If the aims of this project are achieved, we will advance scientific knowledge of the roles of metal ions in each DNAzyme investigated and how different structural features influence the enzyme activity. It will bring our level of understanding of metal ions in DNAzymes closer to that in proteins. It will also allow a unique opportunity to compare and contrast structural and functional properties of the same metal ions, such as Cu2+ or Fe2+, in proteins and in DNA, which will be fascinating because proteins and DNAzymes use very different building blocks. Furthermore, the demonstration of general applicability of the patented catalytic beacon method to sense a wide variety of paramagnetic metal ions (including different oxidation states of the same metal ions) will drive the field of environmental health, allowing on-site, real-time detection of metal ions in environmental monitoring, developmental biology, clinical toxicology, wastewater treatment, and industrial monitoring. Finally, the insight gained from the study on the basic coordination chemistry will shed light on rational design of other types of metal sensors based on organic molecules, polymers or peptides. It will also have important impact on research areas beyond sensor design, such as the design of transition metal-based nucleases and pharmaceutical agents. PUBLIC HEALTH RELEVANCE: Paramagnetic metal ions such as cobalt, copper and iron are beneficial to human health when low in concentration, but are toxic when high in concentration. Developing portable fluorescent DNAzyme sensors for these metal ions will advance the field of environmental health, allowing on-site, real-time detection of metal ions in environmental monitoring, developmental biology, clinical toxicology, wastewater treatment, and industrial monitoring. Insights gained from the study will shed light on rational design of other types of metal sensors and could impact on other research areas such as the design of transition metal-based nucleases and pharmaceutical agents.
DESCRIPTION (provided by applicant): Cost-effective catalytic DNA biosensors for heavy metal ions such as lead(II), uranium(VI), mercury(II), and cadmium(II) will be developed. They will be tested for on-site, real-time detection and quantification with minimal rates of false positive or false negative results. Exposure to these metal ions can cause severe adverse health effects, such as damages to brain, kidneys, and cancers, to human beings, especially children. Current technologies for metal detection employ either expensive or sophisticated instruments or simple sensors, many of which have high rates of false positive or false negative results. Therefore there is an urgent need of reliable portable heavy metal sensors for government inspectors, environmental monitors, household users, clinicians in rural or remote areas, and first-responders in the war against terrorism, where on-site, real-time, and cost-effective detection and quantification are critical and the market for heavy metal detection is estimated to be >$650 million. The project is based on several innovations in the PI's group at the University of Illinois that takes advantage of state-of-the-art tools in catalytic DNA biology, catalytic molecular beacons biotechnology and nanoparticle nanotechnology. Catalytic DNA molecules specific for heavy metal ions will be obtained through in vitro selection, and converted to fluorescent (for quantitative measurement) and colorimetric (for qualitative and semi-quantitative measurement) sensors by combining the DNA with fluorophore/quencher pairs and gold nanoparticles, respectively. The feasibility of transforming the innovations into commercial success at the DzymeTech has been established in the NIH STTR Phase I project (1R41ES014125-01), in which catalytic DNA sensors for lead(II) and uranium(VI) have been obtained that have high sensitivity (e.g., ~ 11 ppt) and selectivity (e.g., > 1 million fold). This Phase II application addresses critical issues of transferring the sensor design into prototypes of sensor kits for markets. The customer requirements will be determined and prototype components and protocols will be developed. They include: "Obtain all four fluorescent and colorimetric sensors for Pb(II), U(VI), Cd(II), and Hg(II). Characterize the sensors by determining the detection limit and selectivity of each sensor. "Design and characterize prototype sensor kits for each metal ion. Including sensor components, storage condition and test protocol optimization, high/low temperature stability tests and reproducibility tests with sensors from multiple-batches. "Test field samples to study interference and matrix effects. Real field samples, including soil and water samples will be collected and tested. Sensor performance with real samples will be used to evaluate the commercialization values of the sensor kits.
PUBLIC HEALTH RELEVANCE: Highly sensitive and selective catalytic DNA sensors for lead(II), uranium(VI), cadmium(II), and mercury(II) will be developed for cost-effective on-site and real-time detection and quantification. Heavy metal ions are widely present in the environment, causing significant health problems such as damages to brain, kidney, and neural system to human beings, especially children. Convenient portable sensors developed in this project will enable government inspectors, environmental monitors, household users, clinicians and first-responders make informed decision about remediation and monitoring strategy and thus improve human health and quality of life.
DESCRIPTION (provided by applicant)
Physiological responses to environmental stressors elevate plasma stress hormones including glucocorticoids, which are well known to cause obesity. Our long-term goal is to prevent obesity caused by environmental exposures. Genistein, an environmental estrogen-like compound found in food sources, has been demonstrated to have anti-obesity properties. However, whether genistein counteracts the deleterious effects of glucocorticoids on metabolic genes, food intake behavior, and fat deposition is not known. The candidate hypothesizes that genistein may prevent glucocorticoid-induced obesity in a rodent model. To test this hypothesis, genes involved in glucocorticoid-induced obesity will be identified in two key metabolic organs: adipose tissue and brain. Similarly, the gene regulatory effects of genistein in these two metabolic control centers will also be determined. In addition, the candidate will investigate whether genistein counteracts the adverse actions of glucocorticoids in metabolic gene networks, food intake, and body fat accretion. To achieve these goals, mice will be treated with vehicle, corticosterone (an endogenous glucocorticoid), genistein, or corticosterone plus genistein. Microarray analysis will be performed to define the regulatory effects of each treatment on gene networks in the hypothalamus and in adipose tissue. In addition, regulation of food intake, blood lipid profiles, body weight, and body fat by each treatment will also be determined. Specific Aim 1 will define glucocorticoid-induced changes in metabolic gene networks and adiposity. Specific Aim 2 will define genistein-induced changes in metabolic gene networks and adiposity. Specific Aim 3 will determine the role of genistein in counteracting glucocorticoid-induced obesity. The candidate anticipates that genistein will counteract glucocorticoid-induced changes in metabolic gene networks, which in turn will result in positive physiological outcomes. Genistein plus corticosterone, compared to corticosterone alone treatment, is expected to yield improved metabolic gene expression patterns and favorable metabolic parameters including body weight. The regulation of representative genes will also be individually verified using real time PCR, radioimmunohistochemistry, or quantitative autoradiographical analysis. The findings of this proposal will improve the understanding of two environmental-related agents, i.e., stress hormones and genistein, and their actions in the multi-level systems regulating energy homeostasis and body weight. These studies will provide a framework to uncover the molecular basis underlying stress hormone-induced obesity and its potential treatment.
DESCRIPTION (provided by applicant): Exfoliative toxin A (ETA) secreted by Staphylococcus aureus causes destruction of human epidermis in bullous impetigo and Staphylcoccal Scalded Skin Syndrome (SSSS), which renders victims vulnerable to life-threatening infections and dehydration. Desmosomes are crucial for cell:cell adhesion in tissues enduring stress, such as the epidermis. These protein complexes anchor intermediate filaments to celhcell junctions, providing the mechanical strength necessary for the skin to serve as the body's first line of defense against environmental insults. Previous work has shown that ETA cleaves desmoglein 1 (Dsg1), a desmosome component and the predominant cadherin of the superficial epidermis. The proposed research will determine the specific molecular consequences of Dsg1 cleavage by ETA that contribute to SSSS. In particular, the toxin's effects on trafficking of and interactions among desmosomal components will be investigated as mechanisms reducing adhesion in keratinocytes; as well, a decoy Dsg1 ectodomain will be evaluated as an ETA inhibitor in vitro and in epidermal equivalents. The results will provide a more complete understanding of SSSS pathogenesis and will identify novel therapeutic targets for treatment of a toxin-mediated disease.
DESCRIPTION (provided by applicant): Asthma is a complex disorder influenced by the interaction of genetic and environmental factors such as exposure to allergens, infections, and air pollution. Excessive Th2 biased immune responses to environmental antigens are thought to cause pulmonary inflammation, airway eosinophilia, mucus hypersecretion and airway hyperreactivity (AHR), cardinal features of asthma. Recent studies have shown that regulatory T (Treg) cells play an important role in controlling the pathogenic immune responses seen in asthma, and the development of Treg cells is thought to protect against asthma. Although therapies that induce Treg cells would provide a cure for patients with asthma, little is known about how to induce Treg cells, how Treg cells develop, or how they suppress allergic immune responses. In order to improve the treatments for asthma and to develop strategies that might routinely induce Treg cells that suppress inflammation in asthma, further understanding of the mechanisms controlling the development and function of these cells is required. Preliminary experiments in our laboratory (see preliminary results section) have shown that in the absence of Ikaros, a transcription factor expressed in early T-cell progenitors as well as in mature T cells, the development of CD25+Foxp3+ Treg cells is significantly reduced. In addition, the production of IL-10, a critical cytokine normally secreted by both Treg cells and dendritic cells that induce Treg cells, is greatly reduced in Ikaros-/- T cells. This suggests that Ikaros critically regulates the development of Treg cells as well as the production of IL-10. The goal, therefore, of this proposal, is to study the role of Ikaros in the development of Treg cells that protect against allergic asthma. In Specific Aim 1, we will examine the molecular mechanisms of Ikaros as a transcription factor that controls 1110 gene expression. In Specific Aim 2, we will use in vitro proliferation assays to compare purified Ikaros-/- and wild type Treg cells in order to investigate if Ikaros regulates Treg cell function. Finally, in Specific Aim 3, we will examine the function of Ikaros in an in vivo mouse model of asthma, to demonstrate how lack of Ikaros in Treg cells impacts airway inflammation and AHR induced by common environmental antigens. Asthma is a complex disease that occurs due to a combination of environmental and genetic factors. The breakdown in normal regulation of the immune system is of major significance in the development of this disease. Regulatory T cells play an important role in controlling the immune response and thus, it is of therapeutic importance to further understand the mechanisms controlling regulatory T cell function.
DESCRIPTION (provided by applicant): This project aims to identify possible environmental endocrine disrupters working by an unusual mechanism that operates after the interaction of ligands with nuclear hormone receptors, namely, by the direct inhibition or potentiation of the nuclear hormone receptor/coactivator interaction itself. This goal will be accomplished by developing time-resolved fluorescence assays that probe in a robust and reliable manner the interaction of the nuclear receptors with coactivators. These assays are adaptable to high-throughput screening, and will be used at the Emory University Molecular Libraries Screening Center, an NIH-funded Roadmap Research Resource to which we have obtained access, to identify possible coactivator binding inhibitors (CBIs) or coactivator binding potentiators (CBPs) that might be present in the environment. After compounds have been identified as possible disrupters or potentiators of endocrine function, they will be subject to secondary assays to confirm that they indeed act through these unusual CBI or CBP mechanisms. These assays will also use fluorescence resonance energy transfer methodology, but with carefully selected alterations in the concentrations of integral components to elucidate mechanism. Finally, cell-based assays such as mammalian-2-hybrid, cotransfection reporter gene assays, or monitoring of hormone-responsive gene products will more definitively demonstrate the possible biological or physiological effects arising from exposure to these compounds. This project should help pinpoint a novel endocrine disruption site within the nuclear receptor signaling pathway and identify the compounds that work at this level. It should also help identify possible CBIs or CBPs present in the environment or in commonly used products that could be causing alterations in the pattern of genome transcription by an unusual mechanism, due to the interruption or the potentiation of nuclear receptor-regulated signal transduction that operates at a post ligand-receptor interaction level. Ultimately, this project should help in identifying harmful compounds present within our environment and, hopefully, guide measures to minimize exposure of the public to these substances.
Endocrine disrupters are exogenous compounds that interfere with the endocrine system, altering hormone action and the messages it sends throughout the body. This project aims to identify possible endocrine disrupters that act by an unusual mechanism. Large numbers of compounds will be screened to determine structural features of those that inhibit or potentiated endocrine action by this unusual process. With this information, steps could be taken to minimize human exposure to these novel types of endocrine disrupters.
Crisp Terms/Key Words: endocrine disrupting compound, small molecule, predoctoral investigator, environmental exposure, nuclear receptor, high throughput technology, molecular biology information system, fluorescence resonance energy transfer, technology /technique development, estrogen receptor, receptor binding, intermolecular interaction, time resolved data
DESCRIPTION (provided by applicant): The environment contains a large number of toxins that adversely affect the health of humans. These toxins range from inorganic compounds such as lead and asbestos to microbial toxins such as afiatoxin and staphylococcalenterotoxins involved in food poisoning. Environmental bacteria in particular represent a large reservoir of agents capable of producing diverse toxins with the potential to affect human health. Genome sequencing has nicely defined the core set of invariant chromosomal genes carried by many of these organisms, but a substantial amount of genetic information varies from strain to strain in the form of genomic islands and remains undefined. These genomic islands may represent 10-20% of the total genetic information carried by some environmental bacteria. Many of these genomic islands encode toxins and other virulence determinants that have the potential to adversely affect human health. Pseudomonas aeruginosa is an environmentally ubiquitous bacterium that causes disease in both plants and animals, including humans. Humans frequently become colonized with P. aeruginosa following ingestion of contaminated environmental sources such as food or water. Although this colonization is typically unapparent and short-lived, in patients who are compromised in some way, P. aeruginosa frequently emerges to cause life-threatening infections. In fact, P. aeruginosa is the leading cause of pneumonia in mechanically ventilated patients and is associated with mortality rates as high as 70%. To cause such severe disease, P. aeruginosa produces a plethora of toxins, but the true breadth of virulence factors produced by this bacterium is unclear. We hypothesize that novel genomic islands of the environmental bacterium P. aeruginosa encode a number of previously uncharacterized virulence factors. In this application, we propose to employ a targeted strategy to identify novel genomic islands in P. aeruginosa. The islands will then be sequenced, and the genes they carry that affect virulence in animals and plants will be identified. It is anticipated that a number of these genes will encode novel toxins or novel export systems that secrete toxins. Successful completion of these aims will identify novel factors produced by the environmental bacterium P. aeruginosa that have the potential to adversely affect human health. Relevance: Pseudomonas aeruginosa is a common environmental bacterium that produces a large number of toxins. We propose to identify additional factors produced by this bacterium that have the potential to harm humans. Identification of these factors will lay the foundation for the development of therapeutic interventions that block the action of these factors and thereby improve human health.
DESCRIPTION (provided by applicant)
This is a proposal to continue funding of the research Training Program in Environmental Toxicology. Established in 2000 to help recruit new scientists into this important discipline, the Program educates pre- and postdoctoral trainees in reproductive, developmental and endocrine toxicology. Outstanding new faculty members will join the Program as preceptors, resulting in a total of 14 members from six departments (Animal Sciences, Chemistry, Crop Sciences, Food Science and Human Nutrition, Molecular and Integrative Physiology and Veterinary Biosciences) in three colleges (Liberal Arts and Sciences, Agriculture, Consumer and Environmental Sciences and Veterinary Medicine). Research disciplines range from neurobehavioral effects of environmental endocrine disruptors to molecular toxicology of the estrogen receptor. The 14 preceptors are a subset of a larger group of 35 faculties who participate in the interdisciplinary Environmental Toxicology Program. This Program, in existence since the 1980s, focuses on training doctoral students from a wide range of disciplines in Environmental Toxicology. The Program includes a weekly seminar series and a broad range of graduate level courses in toxicology. In addition to their departmental requirements, all postdoctoral trainees will take basic toxicology and at least one other advanced toxicology course related to their field of study. Postdoctoral trainees will conduct independent research in toxicology. All trainees attend weekly toxicology research seminars, participate in the toxicology journal club and take a course on research ethics in toxicology. Trainees will be required to present and discuss their research in the seminar and strongly encouraged to present their research at national meetings. Preference will be given to pre-doctoral trainees in their first or second year. Selection will be based on academic success, relevance of proposed research to Program goals and commitment to toxicology. This effort to recruit under-represented minorities will continue.
DESCRIPTION (provided by applicant): There is a clear association between exposure to air pollution and cardiac and respiratory health. Variation in the levels of a component of air pollution, particulate matter (a mixture of particles and liquid droplets), correlate with an increase in asthma and COPD exacerbations and cardiac events. We have shown that particulate matter-exposed macrophages induce fibroblast to myofibroblast transformation, a key phenotypic change of airway remodeling which can lead to irreversible airway disease. We hypothesize that particulate matter induces airway remodeling via oxidant-mediated macrophage release of cytokines that trigger myofibroblast differentiation. Exploring the mechanisms of particulate matter-induced airway remodeling is important in providing preventative and therapeutic targets that apply to a broad range of patients.
DESCRIPTION (provided by applicant): Chemical agents can induce cancers by causing mutations in genes that control important checkpoints of cell division. The immune system has evolved to counter these mutations by recognizing mutated proteins and eliminating the cells that carry them. These mutated "self" proteins can serve as antigenic targets for the action of T lymphocytes. One of the fundamental problems in chemical carcinogenesis is that these mutations may not elicit the required T cell response, thereby leading to uncontrolled growth of some cancers. In this proposal, T lymphocytes will be "engineered" against such cancers. The approach will use a BALB/c mouse model of T cell therapy against a chemical-induced tumor called CMS5. CMS5 expresses a mutated MAP kinase with a single mutation (Lys to Gin) in a peptide that binds to the class I MHC molecule Kd. This peptide/MHC (tErk1/Kd) acted as the antigen recognized by the T cell clone C18. The T cell receptor (TCR) from clone C18 has been expressed previously in transgenic mice. The goal of the present work is to engineer mutants of the C18 TCR with higher affinity for tErk1/Kd and to express the high-affinity TCRs in T cells. My hypothesis is that T cells expressing higher-affinity TCRs will be more effective in the elimination of chemical-induced carcinomas. The specific aims are to: 1) generate TCRs that bind with high-affinity to the chemically induced tumor antigen tErk1/Kd, using in vitro engineering; 2) transfect in vitro engineered TCR genes into T cells and assess their sensitivity to the chemically induced tumor and to specific peptide variants; 3) investigate the in vivo anti-tumor response of adoptively transferred T cells bearing high-affinity TCRs against the chemically induced tumor.
DESCRIPTION (provided by applicant): Acute leukemias result when the regulation of the normal hematopoietic process goes awry at the stem cell or progenitor levels. Benzene (BZ) is an aromatic hydrocarbon in widespread use as an industrial chemical, and is known to play a causative role in the development of certain cases of acute myeloid leukemia (AML). The leukemogenic properties of BZ and its metabolites are thought to occur via effects on normal hematopoietic precursors, but the precise cellular events responsible for benzene-induced leukemogenesis remain unknown. One group of proteins that are potential candidates for such causative effects is the protein kinase C (PKC) family of serine-threonine kinases. These kinases are activated by a wide range of stimuli, including BZ and oxidative stress, and exhibit context-dependent and isoform-specific effects on cell proliferation and differentiation. This proposal will examine the expression and functional roles of the PKC family of proteins in normal hematopoiesis and will determine whether abnormalities in the expression of PKC proteins contributes to the development of AML, including AML related to benzene exposure. Specific aim A is to determine the role of the PKC family in normal hematopoiesis. Studies will be performed to define the expression of different PKC-isoforms during early and late stages of normal erythropoiesis and myelopoiesis, and to examine the effects of disruption of their expression or inhibition of their kinase activities on hematopoietic progenitor cell growth and differentiation. Specific aim B is to determine the role of the PKC family in AML. The patterns of expression of PKC members and their contribution to leukemogenesis will be investigated in primary leukemic progenitors from the bone marrows of patients with AML and will be correlated to prior exposure to benzene. Project relevance: Environmental exposures to benzene and other carcinogens can lead to the development of different forms of AML, thus understanding the mechanisms by which such carcinogens promote the onset of leukemic phenotypes is an essential step towards the development of novel therapies and the prevention of such leukemias. Among the known cellular targets of benzene is the PKC family of proteins, but very little is known about the expression and pathogenetic role of these kinases in benzene-related cases of acute leukemia. This proposal is a comprehensive approach to examine the function of PKC isotypes in normal hematopoietic progenitors and to identify abnormalities in their expression in AML, thereby providing valuable information on the mechanisms by which environmental carcinogens promote leukemogenesis and leading to the identification of novel targets for acute leukemia treatment.
DESCRIPTION (provided by applicant) :
OAI, Inc. and its Consortium are responding to three programs of the NIEHS Worker Health and Safety Training Cooperative Agreement, RFA-ES-04-005: Hazardous Waste Worker Training (HWWT) Program; ; Minority Worker Training (MWT) Program; and Brownfields Minority Worker (BMWT) Program. The total amount requested for each program is as follows:
The overall research objectives of the FRIENDS Children's Environmental Health Center are to: (1) study the impact of exposure to polychlorinated biphenyls (PCBs) and methylmercury (McHg) on cognitive, sensory and motor development of children, (2) develop effective educational strategies to reduce exposure to these neurotoxic contaminants, and (3) undertake laboratory studies to better understand the mechanisms by which these contaminants induce neurological deficits in children. The Center will build on several long-standing research collaborations and will be organized around an exposure cohort that is already being recruited. The cohort consists of Hmong and Laotian refugees who are consuming PCB- and MeHg- contaminated fish from the Fox River in northeastern Wisconsin. The Center includes an administrative core, a community-based project, two biomedical research projects and an analytical toxicology core. The two primary goals of the community-based project are: (1) to evaluate the impact of PCB and MeHg exposure on reproductive health and child development and (2) to provide families with practical information that will help them to reduce their exposure to PCBs and MeHg. The assessments of the children will focus on specific aspects of behavioral and sensory function that have not been adequately addressed in previous human studies. These goals will be accomplished in partnership with community resource groups in the area. The biomedical research projects will complement the community-based project by characterizing the cognitive, sensory, motor and neurochemical effects of exposure to PCBs alone, MeHg alone or PCBs and MeHg combined in a rodent model. Moth projects will used a mixture of PCBs that models the PCB congener profile in Fox River fish, and a ratio of PCBs to MeHg similar to that found in the fish. The findings from the animal studies will guide the selection of additional behavioral and sensory endpoints for use in the children exposed to PCBs and MeHg via maternal consumption of Fox River fish. The analytical toxicology will formulate the PCB mixture to be used in the animal studies and provide congener specific PCB analysts, heavy metal analysis, and pesticide analysis in human and animal samples from the three research projects. The administrative core will provide oversight, coordination and integration of all Center activities.
DESCRIPTION (provided by applicant)
This is a proposal for funding to support a 1.5 day symposium that would be held at the annual meeting of the Neurobehavioral Teratology Society (NBTS), June 29-July 2, 2008 in Monterey, CA. NBTS will meet jointly with two "sister" societies, the Teratology Society (TS) and the Organization of Teratology Information Specialists (OTIS) whose members will also have the opportunity to attend the symposium. The symposium will focus on neurodevelopmental effects of pesticides and metals and will bring together some of the leading epidemiologists and laboratory animal scientists studying these exposures. One two-part session would feature new epidemiological research from prospective birth cohort studies examining agricultural pesticide exposures, urban indoor pesticide exposures, and exposures to metals including lead, mercury and manganese. Confirmed speakers include Dr. Brenda Eskenazi, Dr. Virginia Rauh, Dr. Mary Wolff, Dr. Elaine Faustman, Dr. Robert Wright, Dr. Kim Dietrich, Dr. Jerry Reiter and Dr. Irva Hertz- Picciotto. A second session would highlight parallel research addressing similar exposures in animal models. Confirmed speakers include Dr. Edward Levin, Dr. Barbara Strupp, Dr. Deborah Rice, Dr. Jason Richardson and Dr. Tim Maher. The goal of the proposed symposium is not only to convey the newest research findings on pesticides and metals, but also to bridge the gap between human and animal research perspectives. The symposium is timely because the neurodevelopmental risks from early pesticide exposure in human populations are just beginning to become known. Similarly, the focus on new issues related to metal exposures including the potential role of mercury in autism spectrum disorders, the role of early lead exposure in later antisocial behavior, and the role of gene-environment interactions in metal neurotoxicity is very timely. Bringing together epidemiologists and animal researchers focused on the same exposures and developmental outcomes will provide each of these research communities with a broader perspective and create fertile ground for the development of research collaborations. A majority of the speakers are not members of NBTS, TS or OTIS and do not regularly attend this meeting. This symposium will provide an opportunity for them to present their research to a new audience and get their input. Proceedings of the symposium will be published in the journal Neurotoxicology and Teratology as a series of three peer-reviewed articles. Each will summarize, integrate and discuss the findings presented in one of the three sessions on: (i) pesticides, (ii) metals and (iii) animal models of pesticide and metal exposure. Since much of the research that will be presented focuses on under-represented minority populations the Society will advertise widely at nearby college campuses, particularly those with high percentages of minority students and will waive conference registration fees for any minority students interested in attending the symposium.
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