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Record Count: 16
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header (Title, Principal Investigator, Institution, City, ST, Award Code, or
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DESCRIPTION (provided by applicant): Certain chromium compounds are environmentally and occupationally important human respiratory carcinogens that are mutagenic and carcinogenic at exposure levels which induce some growth arrest and apoptotic cell death. A growing body of evidence indicates that interference with DNA replication is not only a proximal stimulus for carcinogen-induced terminal growth arrest and apoptotic cell death, but may also instigate genomic changes which contribute to the early stages of neoplasia in the progeny of cells which have escaped cell death, We made the initial discovery that chromium-induced DNA-DNA interstrand crosslinks (Cr-DDC) are present in chromate-exposed cells and cause guanine-specific polymerase arrest (PAL) in in vitro replication systems. In the last grant period we made significant progress in studying the formation of this lesion and some of its biological consequences. Based on those studies we have formulated the following over-riding hypothesis: Cr-DDC are polymerase-stalling lesions that activate DNA repair pathways, which generate double-strand break (DSB) intermediates and induce key cellular survival pathways including recombination. Thus, the major objective of this research is to investigate the formation, repair, and biological and molecular consequences of chromium-induced polymerase arresting lesions, in yeast and human cellular/genetic paradigms that allow us to understand the contribution of these lesions to cellular stress and survival responses, The aims for the next period are (i) to conduct further biochemical analysis of Cr-induced polymerase arresting lesions, and to test the hypothesis that direct Cr-DNA binding and/or base oxidation is critical or sufficient for the formation of this base-specific lesion, (ii) to test the hypothesis that Cr-DDC (polymerase arresting lesions) and/or repair intermediates have a critical role in cellular toxicity and/or triggering survival responses. (iii) to mechanistically apply Differential Expression Profiling (DNA MicroArray Gene Chip technology) to decipher survival and repair pathways that are activated when key DNA repair genes are missing, and (iv) to test the hypothesis that recombination is activated by Cr-DDC/PAL (in both cellular and in vitro recombination systems), and is critical to the survival of genetically damaged cells. This research will help elucidate the molecular mechanisms of chromium toxicity and carcinogenesis and will have practical value in contributing to the evaluation of risk to humans in contact with chromates.
Crisp Terms/Key Words: environmental exposure, microarray technology, apoptosis, DNA damage, environmental toxicology, tissue /cell culture, respiratory epithelium, oxidation, DNA repair, DNA replication, chemical carcinogenesis, respiratory neoplasm, environment related neoplasm /cancer, chemical related neoplasm /cancer, chromium, crosslink
DESCRIPTION (provided by applicant):
Chronic arsenic exposure endangers millions of people with skin alterations, peripheral vascular disease, and cancer, including skin, lung, and bladder cancer by, in part, altering gene expression. Increasing evidence demonstrates that epigenetic mechanisms could regulate gene activation or silencing. Therefore, epigenetic regulation could be a part of the mechanisms for arsenic-induced toxicity. Poly(ADP-ribose) polymerase-1 (PARP-1) covalently modifies histones with poly(ADP-ribose), a negatively charged polymer. Poly(ADP-ribosyl)ation of nucleosomal histones alters chromatin structure and is thus thought to regulate chromatin template-dependent processes including gene transcription. Recently, PARP-1 has been shown to regulate stress-induced gene transcription. The overall hypothesis is that chromatin-associated PARP-1 covalently modifies nucleosomal histones with poly(ADP-ribose), and poly(ADP-ribosyl)ated histone(s) epigenetically regulates gene transcription in response to arsenite. The specific aims are to (1) determine the level and patterns of poly(ADP-ribosyl)ated histones in response to arsenite exposure, (2) elucidate the cellular mechanism that can alter the level of pADPr-histones in response to arsenite, (3) determine poly(ADP-ribosyl)ated histone(s) at the chromatin promoters of arsenite-induced target genes, and (4) determine the impact of a PARP enzymatic inhibitor on other arsenite-induced epigenetic markings. The significance of the proposed studies is to offer new insights into the epigenetic mechanism(s) by which poly(ADP-ribosyl)ation of histone(s) may regulate and be regulated to achieve stress response gene transcription in response to arsenite exposure. This mechanism of poly(ADP-ribosyl)ation may be especially adapted to facilitate sudden bursts of efficient transcription activity and therefore is critical for the outcome of environmental exposure.
DESCRIPTION (provided by applicant)
Endocrine disrupters are thought to be an underlying risk factor for the high incidence of hormone related diseases such as early puberty onset and breast cancer. Estrogens play a central role both in the onset of puberty and the etiology of breast cancer. Because estrogen receptor-alpha (ER-a) mediates many of the effects of estrogens, molecules that can bind to and activate ER-a can potentially advance the onset of puberty and increase the risk of breast cancer. Published studies from this laboratory demonstrate that the metalloid arsenite activates ER-a through a high affinity interaction (KI = 10-10 M) with hormone binding domain of the receptor involving amino acids C381, C447, H524, K529 and/or K531, and N532. More importantly, it has been shown that an environmentally relevant dose of arsenite mimics the effects of estradiol on the growth and expression of genes in MCF-7 breast cancer cells. Preliminary data presented in this application demonstrate that environmentally relevant doses of arsenite also mimic the effects of estrogens in vivo. In ovariectomized animals, arsenite increases uterine wet weight and induces estrogen regulated genes. In intact animals, prepubertal exposure to arsenite accelerates the development of the mammary gland and increases the incidence of mammary tumors in animals challenged with the chemical carcinogen dimethylbenzanthracene, consistent with an estrogen like effect on mammary tumorigenesis. Based on these observations, this application will test the hypothesis that early life exposure to environmentally relevant amounts of arsenite imprints or reprograms gene expression in the mammary gland leading to early onset of puberty and increased susceptibility to mammary tumorigenesis. Specific Aim 1 will identify genes altered by prepubertal exposure to arsenite and determine whether their expression is altered through epigenetic mechanisms. Specific Aim 2 will determine whether in utero exposure to arsenite alters gene expression.
Crisp Terms/Key Words: animal puberty, laboratory rat, gene induction /repression, growth /development, arsenic, breast neoplasm, cancer risk, pregnancy, early experience, estrogen receptor, precocious puberty, mammary gland, neoplastic process, environmental exposure, endocrine disrupting compound, epigenetics
DESCRIPTION (provided by applicant): Elevated in utero hormonal environment may increase later susceptibility to develop breast cancer, both in human and rodent models. Our goal has been to identify dietary components that, when fed to pregnant rat dams, results a reduced mammary tumorigenesis among female offspring. Thus, we fed pregnant rats flaxseed diet that contains lignan secoisolariciresinol (SDG), n-3 polyunsaturated fatty acids (PUFAs) and fiber, all that have been linked to reduced breast cancer risk and that potentially reduce serum estrogens. However, we found that female offspring of dams fed 10% flaxseed diet or 15% defatted flaxseed diet during pregnancy were at an increased risk of developing DMBA-induced mammary tumors. This was surprising since their mammary glands contained less targets (terminal end buds, TEBs) for malignant transformation, as also reported by other investigators. The protein component of flaxseed accumulates heavy metal cadmium to the levels exceeding the maximum guidelines set by the World Health Organization. Since cadmium is an endocrine disrupter and activates the estrogen receptor, and it also impairs the ability to repair DMA damage, we hypothesize that in utero exposure to cadmium in flaxseed increases later breast cancer risk. Our study has the following specific aims: (1) determine whether in utero cadmium exposure increases later mammary tumorigenesis; (2) determine whether the presence of lignan SDG, fatty acid n-3 PUFA or fiber modify the effects of in utero cadmium exposure on mammary tumorigenesis; and (3) compare changes in DMA damage repair, including expression of tumor suppressor genes Brcal and p53, and estrogen-induced signaling pathways in rats exposed to flaxseed, cadmium or a combination of cadmium, SDG, n-3 PUFA and fiber in utero. Dietary levels of SDG, n-3 PUFA and fiber will be similar to those present in 10% flaxseed diet. The model system we will use is Sprague Dawley rat exposed to carcinogen DMBA that results mammary tumors that are biologically similar to human breast cancers. Results obtained in this study will provide insight into the mechanisms by which in utero exposure to flaxseed can alter later susceptibility to develop mammary tumors. In particular, we will determine whether in utero exposure to cadmium present at high levels in flaxseed, is the key mediating factor, and whether flaxseed/cadmium's effects involve changes in estrogen receptor signaling or oxidative damage repair or both.
Crisp Terms/Key Words: p53 gene /protein, brca gene, female, embryo /fetus toxicology, dietary supplement, nutrition related tag, dietary mineral, dietary fiber, pathogenic diet, developmental nutrition, DNA repair, carcinogenesis, cancer risk, breast neoplasm, hormone related neoplasm /cancer, cadmium, unsaturated fatty acid, laboratory rat
DESCRIPTION (provided by applicant): HYPOTHESIS: Central nervous system dysfunction is a central pathogenic mechanism in the CFS spectrum of illnesses. Cerebrospinal fluid provides a "window" into potential dysfunctional regulatory, innate immune, and neurological pathways. Neurons, glial cells, epithelial choroid plexus and leptomeningeal cells may be sources of CFS-related proteins. Despite the diverse clinical syndromes, the CFS-related proteome is the same, suggesting a unified pathogenesis. DATA: We have performed tandem mass spectrometry (MS-MS) on cerebrospinal fluid from CFS and healthy control subjects. Traditional and support vector machine (SVM) learning statistical analyses identified nearly identical CFS-related proteomes. A specific pattern of proteins (biosignature) predicted CFS with a significant odds ratio of 34.5 and concordance of 80%. Amyloidogenic proteins, antiproteases, Ig lambda, heme and Fe scavengers, and regulatory prohormones were associated with CFS. This is the first predictive model of CFS to be defined solely from objective data. PLAN: Recruit a new set of CFS and HC subjects (n=50 per group, "cohort 4") to a cross-sectional "training-test" study design. (A) Perform qualitative MS-MS to identify proteins in all samples of cohort 4. Train the SVM algorithm with cohort 4, then test the output "classifier" on an independent set of 42 samples (cohort 3). Determine the prediction accuracy, sensitivity and specificity of the SVM classifier. (B) Perform quantitative MS-MS on pooled CFS and pooled control samples by labeling one with O16 and the other with O18. Mix the samples and identify peptides (and their parent proteins) with O16/O18 ratios that are significantly higher or lower in CFS than controls. (C) These CFS-related proteins will be measured using novel, high sensitivity, luciferase- fusion protein competition immunoassays. Significant concentrations differences between CFS and control and between the 2 cohorts will define protein biomarkers and their sensitivity, specificity and predictive accuracy. (D) Subjective psychometric and other input variables will be tested by SVM learning to define a highly predictive model of CFS. The subjective results and objective proteomic results will also be analyzed to determine if the biomarkers are highly correlated with fatigue, systemic hyperalgesia, or other components of the CFS spectrum of illness. These methods and biomarkers may be of diagnostic value. They will be useful for assessing longitudinal changes in disease severity, phenotype, or the effects of treatment.
DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of nigrostriatal dopaminergic neurons. The etiology of sporadic Parkinson's disease remains unknown although epidemiologic studies implicate to gene environment interaction. Progress in Parkinson's disease modeling in rodents has been achieved by administration of specific toxicants and through construction of transgenic mice harboring human a-synuclein. The pathogenic linkage between toxicant and a-synuclein appears to lie in their unique capacities to produce oxidative injury. Less well investigated is role of glial-neuronal interactions promoting oxidative damage and death of ventral midbrain dopamine neurons. We hypothesize that neuronal overexpression of \vildtype human a-synuclein triggers ROS that are, in part, defended by local glial anti-oxidant responses. Over time this defense mechanism fails resulting in pathologic a-synuclein misfolding, presynaptic dopamine neuron injury and ultimately cell death. To test each facet of this hypothesis, we engineered a compound transgenic mouse to specifically overexpress human wild type a-synuclein in dopaminergic cells (SYN+/+) on the background of glial depleted glutathione peroxidase 1 (GPX-/-) and an antioxidant promoter-reporter. This compound transgenic animal (SYN+/+::GPX-/-::AREhPLAP) affords the study of and cellular locus of oxidative injury wrought by a-synuclein and the impact of impaired glial anti-oxidant capacity on dopaminergic neuron function and viability. Three Aims have been proposed. Aim 1. The evolution of oxidant injury in human wild type a-synuclein homozygous mice (SYN+/+::AREhPLAP). Aim 2. Synergistic injury in SYN+/+::GPX-/-::AREhPLAP mice: a model of accelerated dopaminergic neuron compromise. Aim 3 In which cell types does restoration ofGpx-1 mitigate environmental toxicant injury in SYN+/+::GPX-/-::AREhPLAP mice. These studies will produce clear and interpretable data concerning the role of glia anti-oxidant defense in oxidative injury elicited by a-synuclein alone and in combination with a known dopaminergic toxicant. The mechanistic information derived may enable new glial-oriented therapeutic initiatives.
DESCRIPTION (provided by applicant)
The IBT and NLC are applying as a consortium for a DOE Worker Training Grant. The long-term goal is to increase worker and community safety, protect DOE facilities and protect vital transportation infrastructure, during the remediation of DOE sites and the transportation of radioactive waste and chemical hazardous waste from DOE sites. The IBT-NLC Consortium will use established partnerships with 8 major trucking and railroad unions, and established relationships with 4 DOE facilities (HAMMER, Nevada Test Site, Savannah River, Oak Ridge) to deliver training to a total of 18,860 workers over 5 years. The target population includes, 1) remediation site workers and supervisors at DOE facilities; 2) construction workers and supervisors involved in the remediation of DOE facilities, including drivers of specialized off-road and waste-hauling vehicles; 3) truck transportation workers and supervisors involved in the transportation of radioactive waste and chemical hazardous waste from DOE facilities; 4) railroad workers and supervisors involved in the transportation of radioactive waste and chemical hazardous waste from DOE facilities. The IBT-NLC Consortium will deliver the following courses that fulfill DOE, OSHA and DOT requirements: Radiological Worker; Hazardous Waste Worker; Hazardous Waste Refresher; Awareness-Level Emergency Response; HazMat Safety and Security; Radioactive Materials Transportation; Construction Safety; Respiratory Protection; Respiratory Protection Refresher; and Off-Road and Materials-Hauling Specialized Vehicle Safe Operation. The Consortium will deliver training through 8 fully equipped training centers and will also provide instructors to present training at DOE project sites and local unions. Training will emphasize participatory adult teaching techniques and will include significant time for hands-on practice and simulated work site activities.
DESCRIPTION (provided by applicant)
The IBT and NLC are applying as a consortium for a HWWT and a HDPT Program cooperative agreement. The total cost over 5 years will be $22,229,917.
The long-term goal is to increase worker and community safety, protect work sites and surrounding communities, and protect vital transportation infrastructure, with respect to the remediation of hazardous waste sites and the transportation of hazardous waste and HazMat via trucks, rail cards, and intermodal shipping containers. The IBTNLC Consortium will use established partnerships with 10 major trucking, railroad and longshore unions to deliver training to 28,473 workers in the HWWT and 2,875 workers in the HDPT, for a total of 31,348 over 5 years. The target population includes remediation and construction workers and supervisors at HazWaste sites, and truck, railroad and longshore workers and supervisors involved in the transportation of HazWaste and HazMat. Under the HWWT the IBTNLC. Consortium will deliver the following types of training that fulfill OSHA and DOT requirements: Hazardous Waste Worker; Hazardous Waste Refresher; Awareness-Level Emergency Response, HazMat Safety and Security; Operations-Level Emergency Response; Construction Safety; and Off-Road and Materials-Hauling Specialized Vehicle Safe Operation. Under HDPT the Consortium will deliver Awareness-Level and Operations-Level Emergency Response and HazMat Safety and Security training with special emphasis on the security of intermodal shipping containers. The consortium will deliver training through 9 fully equipped training centers and will also provide instructors to present training at project sites and local unions. Training will emphasize participatory and adult teaching techniques and will include significant time for hands-on practice and simulated work site activities.
Hazardous Waste Worker Training Program (HWWTP)
DESCRIPTION (provided by applicant)
The International Union of Operating Engineers (IUOE) is proposing to participate in the DOE Training Program. The total first year cost for the DOE program is $1,535,234. The ILJOE's objectives are to train DOE site workers to work safely in hazardous waste cleanup, hazardous materials emergency response, disaster response, and related fields.
The target audience will consist of hoisting and portable and stationary Operating Engineers, other skilled trades workers, managers, scientists, engineers, and other workers at DOE sites who are required to have HAZWOPER and related safety and health training. This will include DOE sites located in Oak Ridge, Tennessee, Richland, Washington, Idaho Falls, Idaho, and Granitesville, South Carolina. Over the five-year period, the IUOE will train 11,272 DOE site workers, Operating Engineers, and other workers, including more management and engineering groups, using its six HAZWOPER and safety and health related courses.
The IUOE will use refresher training as the primary vehicle to alert workers at DOE hazardous waste sites to the most recent safety and health developments, particularly deactivation and decommissioning (D&D) issues and homeland security.
With West Virginia University Safety and Health Extension as a consortium member, this application will expand the use of Advanced Training Technologies to enhance the learning experience of the students. Using the proposed subcontractor, ATL, the IUOE will enhance evaluation and quality control procedures to ensure the highest quality in lUOE's DOE training efforts, including a new instructor observation approach.
The IUOE also proposes to formalize a cooperation with International Chemical Workers Union (ICWU) and Paper, Allied-Industrial, Chemical and Energy Workers International Union (PACE) into an Annual Multi-Awardee DOE Trainers Meeting.
DESCRIPTION (provided by applicant)
The IAFF is requesting $3,017,739 ($2,796,218 direct costs and $221,521 F&A) during the initial budget period and $16,013,182 ($14,837,094 direct costs and $1,176,088 F&A) for the total project period of the Worker Health and Safety Training Cooperative Agreement. The IAFF application includes two of the four program areas; Hazardous Waste Worker Training Program (HWWTP) and Hazmat Disaster Preparedness Training Program (HDPTP).
This application addresses two serious emergency responder needs arising out of the events and aftermath of September 11th. A major outcome of the attacks was the creation of the Department of Homeland Security (DHS). DHS has promulgated new requirements, one of which is the National Incident Management System (NIMS). They also created new requirements for funding which, in turn, are causing a significant training shortfall in the emergency response community.
In order to operate effectively in this new environment, emergency responders require incident command, safety management training at large-scale incidents and advanced training, especially at the Technician level. Each year of the cooperative agreement, the applicant will train an average of 1,000 students in the technician curriculum and train-the-trainer courses. They will also reach an average of 750 students with an adapted incident management course which emphasizes safety management during disaster response.
The IAFF proposes to implement a proven training plan that strongly and forcefully emphasizes occupational safety and health and OSHA-defined responder training as a cornerstone of professional and effective emergency response. This plan relies heavily on a combination of direct delivery and the efficient train-the-trainer approach; uses a combination of the Internet, Advanced Training Technologies (ATT) and regional programs; and provides the estimated attendees with the knowledge and the tools necessary to operate safely and effectively. These programs help to ensure that emergency responders operate safely in the post 9/11 environment.
Hazardous Waste Worker Training Program (HWWTP)
DESCRIPTION (provided by applicant)
The AFSCME Training and Education Institute (ATEI) is applying for $5,086,885 in HWWTP funds to train on prevention of and emergency response to the accidental or intentional release of hazardous materials in AFSCME-represented workplaces. ATEI plans to train 9,425 workers over 5 years in programs required by OSHA's HazWOPER standard and other related activities such as confined space entry and trenching safety. The target population for emergency response training includes 800,000 AFSCME members across the country employed in public works (e.g., waste water treatment, road work) and health care who may be on the front lines of hazmat releases, providing programs in English and Spanish. The applicant will also train school custodians and building maintenance staff to safely identify and correct mold contamination problems.
ATEI will expand its pool of peer trainers by targeting train-the-trainer programs in cities with large populations of underserved workers. They will conduct trainer development activities to increase the range of topics covered and work with six other NIEHS awardees to maximize trainer development. Evaluation and curriculum revision activities will continue with their peer trainers.
ATEI will coordinate with consortium members and other awardees. The University of Massachusetts (UMass), Lowell, will continue to lead the evaluation team's activities, analyze long-term impact of training, and train new worker evaluators. The applicant will partner with the Coalition of Black Trade Unionists (CBTU) to address worker and community concerns about toxic chemical exposure and assist in providing training to CBTU's Community Action and Response Against Toxics (CARAT) Teams. ATEI will work with the International Chemical Worker Union's Consortium on mold prevention/control program, and broadcast a satellite teleconference on mold with HMTRI/Kirkwood Community College. Finally, they will participate in a multi-grantee project to conduct regional conferences and assessments on catastrophic event prevention and preparedness.
DESCRIPTION (provided by applicant)
The Service Employees International Union (SEIU) Education and Support Fund (ESF) and the contractors in its consortium, SEIU Local 1199 NY and the Shirley Ware Education Center (SWEC), are applying for a grant under the HWWTP for 5 years at a total cost of $4,229,261 and the HDPTP for 5 years at a total cost of $1,580,584.
Through the unique access provided to the project by the national network of local unions in the 1.8-million member SEIU, the project proposes to prevent acute and chronic injury and illness among workers who are exposed to hazardous materials and wastes in nonintentional and intentional emergency situations. The project will accomplish this by training a total of 7400 workers in 8-hour awareness-level emergency response, 2900 workers in 4-hour awareness-level refreshers, 600workers in 4-hour hazard communication classes, 500 workers in 24-hour operations level training for confined space entry, and 640 workers in 24-hour hospital-based, operations level emergency response. The target population is employed in a wide range of jobs in acute-care hospitals, road maintenance, and waste water treatment. SEIU represents 375,000 workers in acute care hospitals, 10,000 in highway maintenance and 7,500 in waste water treatment. The target population is employed in 40 states but concentrated in California, New York, Maine, and New Hampshire. Training will be conducted by an existing team of 150 specially-trained rank-and-file worker-trainers. The project proposes to train an additional 96 worker-trainers during the 5-year period. Curricula designed specifically for worker-trainers, and appropriate to the technical knowledge of workers in these industries, have already been developed for the awareness-level training and the operations level training for confined space entry. Existing curriculum will be modified for use by worker-trainers for the 24-hour hospital-based operations level emergency response class. Project consortium staff will provide ongoing support for worker-trainers and will hold annual technical meetings for all worker-trainers. The project will also participate in an annual national multi-grantee conference and hold annual external advisory board meetings.
Hazardous Waste worker Training Program (HWWTP)
DESCRIPTION (provided by applicant)
The International Union of Operating Engineers (IUOE) is proposing to participate in the HWWT and HDPT programs. The total first year cost for the HWWT is $2,451,364; and $1,143,600 for the HDPT. The lUOE's objectives are aimed at continually improving the quality, effectiveness, and efficiency of the HAZWOPER Train-the-Trainer course and underlying network of local union training programs, and adapting to the changing needs of its target populations.
The HWWTP target audience is 260,000 hoisting and portable engineers nationwide who operate and maintain heavy construction equipment; 100,000 stationary (building) engineers responsible for heating, ventilating, and air conditioning, water systems, and critical infrastructure in commercial, industrial, institutional, and residential structures; and workers nationwide in critical infrastructures, such as ports, petrochemical plants, hospitals, schools, and power generating facilities. Over the 5-year period, the IUOE will train 65,560 workers and instructors using its 23 HAZWOPER and safety and health related courses.
The target audience for the HDPTP is the same as the HWWTP, but includes, in addition, 60,000 Transport Workers Union employees that operate subways and public transportation nationwide. Over the 5-year period, the IUOE will train 14,304 workers and instructors using the nine homeland security related courses, including the OSHA Disaster Site Worker courses.
In both programs, the IUOE will explore and pilot the use of Advanced Training Technologies utilizing its consortium members, West Virginia University Safety and Health Extension and Wheeling Jesuit University, to enhance the consistency and efficiency of IUOE training programs, emphasizing "blending learning" in the IUOE 40-Hour HAZWOPER training. With its subcontractor, ATL, IUOE will enhance the evaluation, quality control measures, and use feedback to improve training methods, materials, and delivery.
DESCRIPTION (provided by applicant)
The International Association of Fire Fighters (IAFF) is requesting $1,500,000 during the initial budget period and $7,959,497 for the total period of the HAZMAT Training at DOE Nuclear Weapons Complex Cooperative Agreement. Emergency personnel responding to incidents related to the DOE complex face health and safety challenges involving radioactive and other hazardous materials. Since 1994, an average of 2,200 responders have been injured at hazardous materials incidents annually. Many more suffer serious health effects from toxic exposure associated with fire fighting and EMS response. The effective remedy to combat these challenges is a flexible training program that emphasizes occupational safety and health and OSHA-defined responder training as a key to effective emergency response. The IAFF proposes to continue to implement such a proven training plan. This effort relies heavily on the provision of comprehensive specialized training pertaining to specific response hazards and an efficient Train-the-Trainer approach. It offers course formats which can be customized to the specific hazards faced by a given target audience; uses a combination of the Internet and Advanced Training Technologies (ATT) and regional programs. The estimated 1,000 annual attendees leave the course with the knowledge and the tools needed to implement this program in local fire/rescue departments in and around ten specified DOE sites, as well as other regions upon request. The IAFF is the only national organization serving professional fire fighters and enjoys long standing training partnerships and access with fire/rescue departments across the U.S. Our training curricula are current, focused and ready to be delivered. In addition, we have a highly regarded 85-member professional firefighter/paramedic instructor team trained in using facilitation techniques and problem-based learning to reinforce responder safety and health. It is a state-of-the-art program with a focused safety and health message provided by experienced, committed instructors.
DESCRIPTION (provided by applicant):
Alcohol consumption contributes to 4% of the global disease burden and in the United States is the third leading lifestyle-related cause of death due in part to complications arising from alcohol-induced liver disease (ALD). In addition to obesity, chronic alcohol consumption leads to excessive hepatic free fatty acid (FFA) levels that inhibit ¿-oxidation pathways and ultimately cause liver disease (steatosis, inflammation, hepatomegaly, fibrosis, and cirrhosis). Interestingly, the adverse effects of alcohol on the liver, in humans and in mouse models, appear to be due, in part, to attenuation of the peroxisome-proliferator activated receptor alpha (PPARa). The alcohol-fed Ppara-null mouse serves as an excellent model for ALD observed in humans and underscores the importance of PPARa in protecting against ALD. Additionally, this mouse model has been cited in over 750 publications supporting its significant utility in understanding the role of PPARa. The mechanism of the influence of PPARa will be determined for potential therapeutic intervention strategies on ALD and for the development of biomarkers for early detection of this disease. To this end, the following specific aims were designed: 1) To correlate alcohol-induced liver damage with gene expression and metabolomic biomarkers identified in alcohol-fed Ppara-null mice for the purpose of developing specific ALD biomarkers.; 2) To identify potential epigenetic and post-transcriptional changes associated with decreased PPARa expression in mouse models following alcohol consumption; and 3) To develop toxicogenomic and toxicometabolomic signatures for types of alcohol-induced injury using primary hepatocyte cultures. These aims seek to understand and integrate the histopathological, genomic, and metabolomic alterations associated with ALD for the purpose of developing early biomarkers associated with ALD pathogenesis. Chronic alcohol consumption can lead to alcohol-induced liver damage (ALD) due to the impairment of ¿-oxidation pathways and subsequent development of fatty liver. A key regulator of ¿-oxidation is the peroxisome-proliferator activated receptor alpha (PPARa). Alcohol-fed mice lacking PPARa develop human-like ALD and in this project will be used to develop biomarkers that are indicative of ALD progression.
DESCRIPTION (provided by applicant):
Current studies suggest that several human diseases involve gene-environment interaction. Polychlorinated biphenyls (PCBs) are neurodevelopmental and immunological toxicants in experimental animals treated prenatally. Association with neurobehavioral deficits is found in some but not in all epidemiological studies of environmental exposures, with data suggesting the prenatal period to be the most sensitive. The majority of the studies evaluating the impact of PCBs on chronic health conditions, however, have been epidemiological. The proposed study therefore evaluates prenatal and postnatal PCB exposure in relation to identification of disease biomarkers through particular gene expressions at birth and at early childhood. The purpose of this research is to identify biomarkers for PCB induced diseases through gene expression studies that can be used globally in the future for early diagnosis of diseases in humans following environmental stress. This proposal hypothesizes that exposure to PCBs for individuals in the Michalovce district of the Slovak Republic is associated with diseases caused by oxidative stresses, endocrine disruption, and mitochondrial poisoning. This hypothesis is based on the following observations. First, there are several PCBs and metabolites of PCBs that have been isolated from human blood and tissues, and the gene cytochrome P450 (CYP1A1), which mediates production of OH-PCB by oxidative metabolism, has been found to be 65-fold increased by PCB-77 in cellular studies in vitro in the Pi's lab. Second, these metabolites are able to transmit across the placental barrier and be transferred to the human fetus. Third, with few exceptions, most adverse effects of background levels of PCBs were primarily related to prenatal exposure. Reported effects of background exposures in infants include reduced birth weight, less postnatal growth, impaired development, impaired immune-response, and lower thyroid hormone level. It is unknown whether these effects are caused by the PCBs themselves or by their metabolites. Fourth, high affinity binding of hydroxylated PCBs to Transthyretin (TTR) results in selective delivery of these hormones over the blood-brain barrier and over the placenta to the fetal compartment where they produce a hypothyroid effect. Fifth, in vitro tests with human liver and kidney cells clearly show that PCBs alter gene expression which has been connected with specific diseases. These diseases are not related to non-genetic factors, and Sixth, several animal and epidemiological studies suggest that prenatal exposure to PCBs and related compounds results in lower birth rates. The aims to achieve our goal in this proposal are AIM 1: To refine and confirm prior genome-wide gene expression patterns upon exposure of PCBs or its metabolites in human Peripheral Blood Mononuclear Cells (PBMC) (in vitro) to correlate risk to that of PCBs. AIM 2: To obtain genomic biomarkers of diseases caused by PCBs or its metabolites in early childhood. AIM 3: to validate candidate biomarkers in randomized studies in large scale population studies. The goal would be to improve our ability to study this process in its early stages before the clinical sign arises. These personalized measures of exposures will be combined with genomic information to decipher environmental and genetic risk factors for disease development and progression. Affymetrix oligonucleotide arrays, followed by real-time RT-PCR will be used for human gene expression studies. Epidemiological studies will include the current body burden, and time-dependent changes in congener profiles in longitudinal studies in newborn babies using Slovak population. The Slovak population is the worst hit by the PCBs comparing any other parts of the world. Besides, co-principal investigators have excellent epidemiological database funded by US-NIH, which provide unique opportunities for the proposed genomic biomarkers using PCB-exposed human population. The complementary database will be established to find correlation of PCBs and disease development for comparative statistical analysis. The proposed collaborative studies are expected to facilitate ongoing epidemiological and health effect studies of polychlorinated biphenyls (PCBs) to develop early disease biomarkers and are important for understanding the potential health risk from these compounds in general. This research will also reside with its ability to use non-invasive gene expression tools to study the early pathogenesis of the disease and to help the nation develop early intervention for multiple chronic disease that continue to burden our health system.
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