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Record Count: 14
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header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant):
Due to the their widespread use and stability, sediments contaminated with persistent organic pollutants (POPs) such as polychlorinated biphenyls, chlorobenzenes and dioxins have been an environmental concern for several decades. In addition to perturbing the benthic community, these compounds biomagnify in the food chain through accumulation in the fatty tissue of animals, such as fish and marine mammals, which can eventually affect humans if consumed. Exposure to halogenated POPs by humans can lead to dermal toxicity, teratotoxicity, endocrine effects, hepatotoxicity, immunotoxicity, and carcinogenesis. Although chemically stable in the environment these highly chlorinated compounds are susceptible to degradation once most of their chlorines are removed. The initial dechlorination is catalyzed in the anaerobic environment by microbial reductive respiration; the products of this initial microbial process can then be degraded and detoxified by oxygen respiring microorganisms. The limitations of these processes are: 1) anaerobic dechlorination is often slow and incomplete; 2) aerobic degradation is inhibited by limited availability of oxygen in the anaerobic sediment regions where these compounds persist. The Principal Investigators propose to complete the anaerobic process to unflanked di- through tetrachlorinated by in situ bioaugmention with dechlorinating microorganisms followed by application of low current hydrolysis to provide a constant level of oxygen for the complete degradation of the chlorinated compounds. The innovative aspects of this approach include the use of dechlorinating species with specific activities to direct the anaerobic dechorination pathways, a unique process for scaling up dehalogenating inoculum without co-release of toxic chlorinated compounds, electrolysis of water for maintaining constant oxygen levels during aerobic degradation and high throughput molecular assays for monitoring microbial communities. This integrated approach will optimize both anaerobic and aerobic processes to achieve complete in situ detoxification of chlorinated compounds through mineralization to small molecular weight metabolites and carbon dioxide. Implementation of a tractable in situ detoxification process to organohalide impacted sites will mitigate exposure to the food chain and subsequent exposure risks to the general public.
DESCRIPTION (provided by applicant): Arsenic is an enormous public health problem as it is a contaminant of drinking water in many parts of the world. A number of recent epidemiological studies have correlated arsenic exposure with adverse developmental outcomes such as stillbirths, spontaneous abortions, neonatal mortality, low birth weight, and delays in the use of musculature. Studies in rodents also demonstrate that offspring of pregnant dams exposed to arsenic have increases in preterm death, low birth weight, and changes in locomotor activity. Using a model fish species termed mummichogs, our laboratory has shown developmental abnormalities in offspring exposed to 230ppb arsenic during gametogenesis, which correlated with an upregulation of genes involved the musculature, such as myosin light chain 2, tropomyosin, and parvalbumin. We have also demonstrated that exposure of C2C12 myocyte cells to 20nM arsenic resulted in a delay in myoblast differentiation that correlated to a reduction in myogenin expression and a reduction in methyltransferase expression. Thus, we propose to investigate the mechanisms underlying the increase in developmental abnormalities and changes in myogenesis after exposure to arsenic using the C2C12 cell line. Our hypothesis is that inappropriate expression of transcription factors involved in skeletal muscle development, coupled with altered gene methylation, is a mechanism partly responsible for altered myogenesis and the developmental abnormalities in arsenic-exposed offspring. We will test this hypothesis by exposing C2C12 myoblast cells to increasing concentrations of arsenic to investigate the time and dose-dependent changes in differentiation, multinucleation, muscle-specific genes, and myogenic transcription factor expression by real-time PCR and immunoblotting. To investigate the mechanisms responsible for the lack of differentiation, DNA methylation, methyltransferase activity and expression, and methylation precursors will be examined. Finally, methylation inducers and inhibitors, and transfection of methyltransferase genes will be used to determine whether the myogenic phenotype and myogenic protein expression can be altered. Our laboratory is well positioned to carry out the proposed studies because we have experience in examining the effects of arsenic on development, and on differential gene and protein expression. We have previously been examining phenotypic and gene expression changes after arsenic exposure in a model fish species, and now wish to further our in vivo findings by using a cell model to examine arsenic's mechanisms of action as it relates to altered development and altered myogenesis. PUBLIC HEALTH RELEVANCE: The ultimate benefit of this work is to assess the mechanisms of how environmentally realistic arsenic exposure impacts development, and help to examine whether the drinking water standard for arsenic is protective of human health.
DESCRIPTION (provided by applicant): The overall aim of this project is to identify suspect organic and inorganic chemicals during critical periods of intrauterine exposure that are associated with child developmental disabilities and mental retardation (DD/MR). The study will compare individual level analysis with new spatial and temporal statistical methods to infer from analysis of clusters to individuals about the risk associated with temporal and spatial exposures. The study will be divided into three phases. During Phase I we will test the hypothesis that there are clusters of DD/MR among infants identified by maternal residence during pregnancy. We will link over 152,000 maternal child pairs using Medicaid prenatal and postnatal medical data, and monthly addresses, so clusters of DD/MR can be identified using spatial statistics. During Phase II we will test the hypothesis that soil samples will show variation in toxicity levels that can be used to identify locations with potentially greater concentrations of suspect organic and inorganic chemical which may be associated with DD/MR. This will involve collecting and analyzing soil samples from cluster sites and from comparison areas where rates of DD/MR are not elevated. In addition, we will test the hypothesis that mercury, chromium, arsenic, PCBs, and other selected chemical contaminants will be measured in higher concentration in the higher toxicity soil samples compared to the lower toxicity soils, as identified using Microtox. We will send a subsample of the high and low toxicity soil for chemical analyses at an external analytical laboratory. During Phase III we will test the hypothesis that maternal residence proximal to toxic waste sites with identified chemical exposures, during critical periods of fetal development, will be associated with higher risk for DD/MR in the infant, after controlling for maternal and child risk factors. This will involve the development of statistical methods that combine traditional and spatial procedures to analyze associations between the spatial relationship, temporal exposure (month of pregnancy), and soil samples. These can be used to generate hypotheses about specific environmental exposures associated with DD/MR. This research will be both multidisciplinary and multimethod, with specific emphasis on the development of new techniques, to analyze the complex associations of environmental and medical data.
DESCRIPTION (provided by applicant): Perfluorinated hydrocarbon compounds such as - perfluorooctane sulfonate (PFOS) are emerging contaminants of concern as concentrations of PFOS have been detected in surface water, house dust samples, processed milk, ground beef, and human serum, breast milk, and cord blood. Moreover they are persistent, bioaccumulative, and highly toxicity. Cause for concern is not only driven by the persistence and the documented toxicity, but by the uncertainty and data gaps including mechanisms of effects, exposure routes, kinetics in the body, under representation of populations in the current human biomonitoring data, and lack of understanding of sublethal exposure effects. Many compounds in this class, like PFOS, are PPAR-alpha ligands. We have shown that PFOS and compounds that degrade to PFOS modulate T- dependent antibody production. We speculate that this may occur through the known suppression on IL-6 production by such ligands. We speculate, that a plausible explanation related to PPAR-alpha ligation is through antagonism of NF-kappa B and c-Jun and the resultant inhibition of IL-6 production thereby resulting in inhibition of IL-6 stimulation of IgM production. Hypothesis: PFOS modulates antibody production through PPAR-alpha activation and subsequent suppression of B-cell IL-6 production.Aim 1. To determine the role of PPAR-alpha in the suppression of T-dependent antibody production by PFOS by assessing TNP-KLH antibody responses in wild type (control) and PPAR alpha null mice (129/SvlmJ &129S4/SvJae- Pparatm1Gonz/J mice; respectively). Mice will be treated with 0, 0.5 or 5 mg/kg PFOS over a 28-day period (total dose). Seven days prior to sacrifice mice will be injected with TNP-KLH and at the end of the study serum will be collected to assess TNP-specific IgM. Aim 2. To study possible modes of action of PFOS on T-dependent antibody production by assessing CD40 and CD154 expression, B-cell IL-6 production and T- cell cytokine production (IL-4, IL-5, and IL-6) in B6C3F1 mice. This will consist of two experimental sets where mice will be treated with 0, 0.5 or 5 mg/kg PFOS over a 28-day period (total dose). In Experiment A mice will be injected with TNP-KLH seven days prior to sacrifice. In Experiment B mice will not be immunized. The unimmunized and immunized experiments will be conducted to control for possible differences in response related to lymphocyte activation from the immunization.
DESCRIPTION (provided by applicant): Nutraceuticals are a multibillion dollar industry in the USA. For reasons of both marketing strategy and antidotal evidence, oriental herbals are touted as having great promise for ameliorating a variety of diseases. Oriental herbal supplements are perhaps the best example of products readily consumed by the American public without adequate knowledge of efficacy or safety. As a case in point, an active ingredient in Chinese herbals prepared from Polygonum tinctorium has been isolated that inhibits cyclin-dependent kinases and glycogen synthase kinase thereby inhibiting proliferation of leukemia cells. Extracts from this plant enhance detoxication processes and they have potent antiinflammatory properties. The biological activity of the active ingredient has been traced to an indole-metabolite of tryptophan that is further metabolized to two end products, indigo and indirubin. Indirubin is now known to be the active anti-neoplastic and anti-inflammatory ingredient in Polygonum tinctorium extracts. Indirubin binds to the cytosolic aryl hydrocarbon receptor (AhR), a transcription factor, with high affinity and activates the translocation of the ligand-receptor complex to the nucleus, leading to the expression of a suite of genes. Surprisingly indirubin binds to the AhR with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like affinity. High affinity binding of indirubin to the AhR is an alarming observation because most agents that bind with high affinity to the AhR are immunotoxic. Our preliminary data show that indirubin is a potent inducer of CYP1A1 in differentiated human macrophages. Furthermore indirubin potentiates LPS-stimulated macrophage activation. In addition, indirubin alters the expression of indoleamine 2, 3-dioxygenase (IDO), an enzyme not yet described as being linked to AhR activation. IDO modulation by indirubin is intriguing because several recent studies confirm that tryptophan metabolism and reduction by IDO-alters T-cell responses. Taken together with other preliminary data, including gene array analysis, RT-PGR and protein expression profiles, it appears that indirubin has the potential to act as a TCDD-like compound. To date information regarding potentially adverse effects of novel plant-derived AhR ligands like indirubin on immune function is lacking of particular importance to immune function, cellular and molecular events involved in macrophage differentiation and activation leading to altered proinflammatory events may be affected by plant-based AhR- ligands. The following proposal tests the hypothesis that indirubin is a potent immunotoxic compound.
DESCRIPTION (provided by applicant):
TCDD (dioxin) is an environmental contaminant that has given rise to major human health concerns. It belongs to the family of halogenated aromatic hydrocarbons (HAH) and is considered the most toxic chemical ever created. The immune system is highly susceptible to the toxic effects of TCDD with marked effect on thymus and T cells. Recent studies from our lab demonstrated for the first time that TCDD can induce apoptosis in thymocytes and T cells in vivo involving Fas-Fas ligand (FasL) interactions. We found that Fas- and FasL-deficient mice were more resistant to TCDD-mediated immunotoxicity when compared to the wild-type mice. Because human subjects with similar mutations in Fas and FasL have been identified, our results suggested differential responsiveness to dioxin-like toxicants in the human population to immunotoxicity. Fas-FasL interactions play a critical role in T cell maturation and differentiation. Thus, any interference in these interactions can lead to autoimmunity and altered immune response to infectious agents or cancer. Thus, in the current study, we will test the central hypothesis that TCDD perturbs the development of cell repertoire by interfering with the Fas-FasL interactions in the thymus. To this end, we will pursue 5 specific aims: In aim 1, we will test whether TCDD induces apoptosis in T cells of the thymus of C57BL/6 mice through death-receptor (Fas) or the mitochondrial pathway either independently or through cross-talk. In addition, the possible role played by ER stress pathway, the third novel apoptotic pathway, will also be investigated. In aim 2, we will investigate if the interaction between T cells and stromal cells involving Fas and its ligand is responsible in induction of apoptosis in T cells using adoptive transfer of hematopoietic stem cells. In aim 3, promoter region of Fas and FasL genes will be analyzed to characterize the mechanism(s) through which TCDD induces the expression of Fas and FasL. In aim 4, we will use fetal thymic organ cultures derived from Fas-deficient and FasL-defective mice to analyze the apoptotic pathways using cDNA arrays. In aim 5, the effect of prenatal exposure to TCDD on positive and negative selection of T cells in the developing thymus will be studied using TCR transgenic mice. Together, the current study should provide novel information on how prenatal and postnatal exposure to TCDD would alter the T cell repertoire by interfering with the apoptotic pathways.
Crisp Terms/Key Words: mitochondrial disease /disorder, microarray technology, terminal nick end labeling, p53 gene /protein, BCL2 gene /protein, proteasome, cysteine endopeptidase, apoptosis, SDS polyacrylamide gel electrophoresis, environmental toxicology, organ culture, T cell receptor, early experience, perinatal, dioxin, immunotoxicity, western blotting, genetic regulation, gene expression, pathologic process, polymerase chain reaction, cell cell interaction, T lymphocyte, thymus, genetically modified animal, laboratory mouse
DESCRIPTION (provided by applicant): The long-term goal of this project is to elucidate the events that cause mitochondrial dysfunction in ischemia/reperfusion- and toxicant-induced acute renal failure (ARF), and to identify a therapeutic approach that prevents the mitochondrial dysfunction and reduces ARF. The role of mitochondrial dysfunction and disruption of Ca 2+ homeostasis in renal cell injury and death has been demonstrated in numerous models of ARF and nephrotoxicity. The importance of calpains (Ca2+-activated neutral cysteine proteases) in renal proximal tubule cellular (RPTC) injury and death produced by hypoxia/reoxygenation and toxicants has been shown using calpain inhibitors. In particular, two dissimilar calpain inhibitors not only blocked hypoxia/reoxygenation RPTC death, but also blocked the mitochondrial dysfunction and promoted the recovery of respiration during reoxygenation. These results strongly support a key role for calpains in mitochondrial dysfunction. The above experiments showing calpain inhibitor protection of mitochondrial function in RPTC, suggest that mitochondria may contain a calpain. In a number of diverse preliminary experiments using isolated renal cortical mitochondria (RCM) we have obtained additional evidence of a novel mitochondrial calpain that is responsible for mitochondrial dysfunction. These data resulted in the hypothesis that mitochondrial Ca 2+- uptake leads to the activation of a mitochondrial calpain, which causes the mitochondrial dysfunction and ultimately results in RPTC death and ARF. The specific aims of this application are: Specific Aim I: Identify and characterize the mitochondrial calpain and examine its regulation in isolated RCM and RPTC. Specific Aim II: Elucidate the mechanism of mitochondrial calpain-mediated mitochondrial dysfunction in RPTC and isolated RCM, and identify the mitochondrial protein targets of mitochondrial calpain. Specific Aim III: Determine the effectiveness of currently described calpain inhibitors on mitochondrial calpain and develop new specific inhibitors of mitochondrial calpain using novel, non-natural amino acid analogues and determine their effectiveness in RPTC and isolated RCM. Specific Aim IV: Determine the efficacy of current and/or developed calpain inhibitors in an in vivo model of mitochondrial dysfunction and ARF. Completion of these Specific Aims will add significantly to our basic understanding of cell injury and death, particularly events mediating mitochondrial dysfunction. Further, we will identify a mitochondrial calpain and develop novel calpain inhibitors, including those that are mitochondrial calpain specific. Ultimately, these studies may lead to the development of therapeutic agents that improve clinical outcomes in patients with ARF.
DESCRIPTION (provided by applicant): Adverse effects associated with acute air pollution exposures have been well studied; however evidence on effects of chronic exposure has mainly been limited to a few seminal studies of long-term exposure to air pollution. These studies found an increased risk of mortality associated with long-term exposure to particulates. A few recent studies have broadened knowledge in this area, demonstrating an association between adverse health outcomes and chronic particulate exposure, even as particulate levels have decreased somewhat over time in many areas of the US. We are currently conducting one of these studies with data from the Nurses' Health Study (NHS), combining improved exposure, covariate and outcome assessment. In contrast to other studies, a complex GIS modeling process estimates particulate exposure for each address for each participant over a number of years. In addition, we are adjusting for potential risk factors using information that is updated every two years. Results indicate significant associations of chronic particulate matter less than 10 microns in diameter (PM10) exposure with all-cause mortality and fatal myocardial infarctions. Previous studies have indicated differences in the effects of air pollution exposure among men and women; therefore a study of chronic exposure among men would contribute significantly to the literature. We propose to apply the exposure modeling methods which have been developed for the NHS to examine in the HPFS the relationships of chronic particulate exposure with all-cause mortality and cardiovascular disease. PUBLIC HEALTH RELEVANCE: Assessing the relationship of chronic particulate exposures to all cause mortality and cardiovascular disease is of great public health significance. This study will add to the current literature by examining these associations among a cohort of men, as recent cohort studies of chronic exposures have focused on women. In addition, the study will take advantage of exposure models that were developed for a previous study and the use of updated covariate information for the entire period of follow-up.
DESCRIPTION (provided by applicant): The long-term goal of the collaboration between the USC and Southern Sun BioSystems is to create a plant breeding and remediation technology-development center which would supply hardware, protocols for breeding-selection and mass production of elite plants for nurseries and remediation businesses, with licensing and tracking mechanisms for protecting intellectual property. This project is built on the successful demonstration of the feasibility of our novel technology for in vitro breeding of a large biomass plant for field-scale phytoremediation. The technology transfer capitalizes on Southern Sun's innovative mass propagation technologies and on somaclonal breeding by amplification of the genetic variation-generating step, that is the number of cell divisions in the totipotent cell cultures subjected to selection. A commercialization plan for elite plant sales and breeding technology is supported by letters of commitment from a variety of remediation and biomass utilizing businesses. Phase II objectives: (1) the frequency and extent of somaclonal variation in second round of culture and (2) preselection using the same pollutant (testing physiological constraints on dehalogenation); (3) add valuable new traits (morphological variations, higher cellulose to lignin ratio) to elite lines from Phase I and (4) to a salt tolerant line; (5) improve mass propagation, transportation, acclimatization by prevention of hyperhydricity; (6) certify elite lines by determining first order detoxification rate constant in hydroponic system, (7) by testing stability of the new traits, and by crop trials to demonstrate remediation of trichlorophenol (and biomass production) of TCP at Southern Sun (8a), and to demonstrate biomass production and remediation of a select pollutant in city sewage sludge at BioTech, Inc., Cayce SC (8b), and potentially in hog lagoons in Clinton, NC. Phase II will produce: elite lines with certified superior haloorganic detoxification ability with added traits to promote end uses, sufficient in vitro stock for mass propagation/field applications, an improved strategic efficiency, cost per unit output, of elite plants for phytoremediation, and pre-booked sales.
DESCRIPTION (provided by applicant)
Airway mucus hypersecretion is a prominent feature of numerous lung pathologies. Determining its role in exacerbation of lung disease by airborne particulates is the focus of this application, as well as future proposals. The primary goal is to unveil signaling pathways altered by asbestos that regulate the expression of hClcal/mclcaS and muc5ac, two genes involved in mucin production and/or secretion. This hypothesis will be tested in three specific aims which encompass both in vivo and in vitro approaches to elucidate signaling pathways that control the regulation of these genes, and their involvement in asbestos-induced mucus metaplasia. The first hypothesis is that expression of mclcaS and development of mucus production will be
depressed in CC10-dominant negative (dn)MEK mice compared to normal mice exposed to chrysotile asbestos via inhalation. Furthermore, Clara cells within the bronchiolar airways will acquire the ability to produce and secrete mucus following asbestos insult. To test this hypothesis, the candidate will observe asbestos-induced gene changes in lung epithelial cells of mice expressing an epithelial cell-specific dnMEK transgene previously characterized in the candidate's current lab. The second hypothesis states that asbestos fibers induce the expression of hClcal and muc5ac by altering epidermal growth factor receptor (EGFR)/mitogen activated protein kinase kinase-1 (MEK)/activator protein-1 (AP-1) signaling pathways through the generation of reactive oxygen species (ROS). The third hypothesis is that the asbestos-induced production of Muc5ac requires the presence and up-regulation of hClcal, and that this induction is dependant upon signaling through EGFR/MEK/AP-1. The experiments for aims two and three will be carried out in human lung epithelial cell lines using inhibitors of MAPK signaling pathways and si (small interference)-RNA constructs. Elucidation of critical genes involved in lung injury following asbestos exposure could aid in the development of therapeutic and prognostic strategies to treat asbestos-associated lung diseases. The long term goal of these studies is elucidating mechanisms of gene regulation by pathogenic environmental contaminants, and how these events lead to diseases such as fibrosis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, and cancer. The hope is that enhancing the basic understanding of these diseases will lead to appropriate risk assessment and future development of therapeutic strategies for airborne related diseases.
DESCRIPTION (provided by applicant): Oxidative stress-induced cell death plays a major role in ischemia/reperfusion (I/R) injury leading to end- organ damage in brain, heart, liver, and kidney. Our previous studies identified a membrane-bound Ca2*- independent phospholipase A2, iPLA2gamma, in mitochondria and endoplasmic reticulum (ER) of rabbit renal proximal tubular cells (RPTC). We revealed that rabbit ER-iPLA2gamma has similar homology to human iPLA2gamma, is present in various tissues vulnerable to oxidative stress-induced injury including brain, heart, and kidney, and is cytoprotective in RPTC during oxidant-induced injury. We propose that ER-iPLA2gamma is protective during oxidative injury by preventing and/or repairing oxidant- induced ER lipid peroxidation, thereby preventing ER membrane disruption and Ca2+ release, and protects renal cells from injury. Because oxidative stress-induced cell death plays a major role in I/R injury, we propose that inhibition of iPLA2gamma in the kidney will potentiate l/R-induced Acute Renal Failure (ARF). Our preliminary studies connect the cytoprotective role of iPLA2gamma during oxidant-induced injury in RPTC to ER lipid peroxidation and ER Ca2+ release. Specific Aim 1 will identify the role of iPLA2gamma in oxidant-induced ER lipid peroxidation, membrane fluidity, and Ca2+ release using isolated ER membranes. In each set of experiments a specific inhibitor of iPLA2gamma, R-Bromoenol Lactone (R-BEL) and its inactive enantiomer (S- BEL, negative control) will be used to evaluate the role of iPLA2gamma in these changes. Specific Aim 2 will elucidate the mechanisms by which ER-iPLA2gamma is cytoprotective during oxidant-induced injury in RPTC. We will measure changes in cytosolic free calcium ([Ca2+f]) and ER Ca2+ stores in response to oxidative stress in the presence and absence of iPLA2gamma inhibition in RPTC, using a Ca2+ fluorescent probe, laser scanning confocal microscopy, and pharmacological tools that modulate ER Ca2+, and link these changes to cell death. Specific Aim 3 will test our hypothesis that iPLA2gamma is protective in vivo using a rabbit model of l/R- induced ARF. Rabbits will be pretreated with R-BEL or diluent control prior to I/R and differences in renal function, morphological damage, and lipid peroxidation will be assessed. Completion of these aims will elucidate the mechanism(s) by which iPLA2gamma is cytoprotective. These studies will help strengthen our understanding of kidney damage and failure. They may help identify therapies for renal failure, stroke, and heart attack.
DESCRIPTION (provided by applicant): Humans, like all organisms, are subject to environmental stresses. To deal with these stresses, such as damage to the DMA or oxidation of proteins and lipids, our cells possess numerous protective mechanisms (e.g. DMA repair or anti-oxidant systems). However, when stresses become too great, our cells are programmed to kill themselves-a process called programmed cell death or apoptosis. Programmed cell death plays important roles in human health and disease; excessive programmed cell death leads to the significant morbidity and mortality associated with ischemic heart disease and stroke, whereas defective cell death leads to the second greatest cause of mortality in the United States, cancer. Sphingolipids are important regulators of cell growth and death. Ceramide, a bioactive sphingolipid, is an essential mediator of programmed cell death. Ceramide is produced by ceramide synthases (CerSes) during cell death, and there is an accumulating body of evidence that these enzymes play specific roles in regulating ceramide generation and cell death. However, the mechanisms of CerS- and ceramide-mediated cell death are ill-defined and warrant further study. By understanding the details of these pathways we will be able to identify targets of therapeutic interest. The goal of this project is to determine the role of CerSS and CerS6 in mediating programmed cell death. This project will utilize the MCF-7 breast adenocarcinoma cell line to investigate the contribution of CerSS and CerS6 to cell death induced by the genotoxic stress ultraviolet light (UVC). In preliminary investigations, the pro-death protein Bax has emerged as a downstream target of CerSS and CerS6- mediated ceramide production in UVC-induced death. The aims of this study are 1) determine how CerSS and CerS6 regulate cell death; 2) determine how CerSS and CerS6 are regulated during cell death; and 3) determine whether CerSS or CerS6-mediated ceramide production is sufficient to activate cell death pathways (e.g Bax). The primary methodology of these studies will be to overexpress or knockdown CerSS and CerS6 and examine subsequent effects on Bax activation and other parameters of cell death. This project represents an incremental step in achieving our long-term goal of determining the mechanisms of ceramide-mediated programmed cell death. Human cells respond to excessive stress by making a decision to kill themselves. This project seeks to determine how the lipid ceramide and the enzymes that make ceramide regulate this decision.
DESCRIPTION (provided by applicant)
Environmental Stress Signaling and Cellular Consequences (ESSCC) result from exposure to environmental xenobiotics, drugs, oxidants, radiation, ischemia/reperfusion, and nutritional imbalances. Despite the diversity of environmental stresses, there is a commonality in the responses of numerous cell types to these insults. Because environmentally and/or xenobiotically mediated diseases and the majority of other diseases incorporate cell injury, death, carcinogenesis, and a diminished capacity for cellular repair and regeneration in their pathology, the need for scientists trained in ESSCC is critical. The objective of the ESSCC Training Program is to train new scientists to address mechanisms of ESSCC and to translate findings into the development of interventions or novel therapeutics that prevent or diminish cell injury, death, and carcinogenesis, and/or promote repair and regeneration. In addition, new scientists entering this area of research will be able to use recently developed genomic, proteomic, and bioinformatic technologies to elucidate mechanisms of ESSCC. The trainees will come from various backgrounds that encompass chemical, physical, and biomedical sciences and will be integrated into the interdepartmental didactic and research ESSCC Training Program. It is anticipated that the training afforded by the ESSCC Program will result in new scientists that address the consequences of exposures to environmental xenobiotics. The primary principle uniting the mentors of the ESSCC Training Program is the universal role of environmental stress signaling and cellular consequences in environmentally and xenobiotically mediated diseases and other diverse diseases, and the belief that cells from different organ systems exhibit many common responses to diverse insults and stresses. It is viewed that advances in understanding ESSCC and training future scientists in ESSCC can be accomplished more quickly through integration of ESSCC efforts of scientists across classic departments and disciplines.
DESCRIPTION (provided by applicant): The proposed research seeks to address critical gaps in the scientific knowledge on the effectiveness of community-university partnerships in empowering vulnerable communities such as environmental justice (EJ) communities to use science to address local public health issues. Unfortunately, there are few examples of federally funded research programs that provide information on research approaches and partnerships appropriate to build trust and confidence of EJ populations in scientific research that effectively addresses their needs. Additionally, few of these programs can act as models to help achieve the long-term objectives of the NIH Public Trust Initiative. We submit that the work of the West End Revitalization Association (WERA) is a good model for the NIH Public Trust Initiative. WERA, a community-based environmental protection organization based in Mebane, North Carolina, founded a community-university partnership to address the lack of basic amenities, environmental injustice, and public health issues in local black communities. WERA developed the community-owned and managed research (COMR) framework as the foundation for its community-university partnership. To assess the value of WERA's community-university partnership in informing and engaging the public, particularly vulnerable EJ populations through scientific research, we will meet the following aims: 1) evaluate the impact of COMR and research and training core of the community-university partnership in improving scientific literacy and community's trust in the research process; 2) assess the impact of the career and pipeline development core of the partnership in improving scientific literacy of local youth and students and their interest in public health research; and 3) evaluate the impact of the collaborative problem solving model core of WERA's community-university partnership in helping to increase scientific literacy, communication, collaboration, trust, and equity between WERA and its partners. The proposed study is novel because it is uniquely positioned to explore WERA's community-university partnership because of the long-term relationship between the investigators. The project is also significant because it will document that scientific literacy, confidence in research process, participation in scientific research, and collaboration did increase in local EJ communities due to WERA's community-university partnership and use of the COMR framework. We believe that the evaluation results will make a positive contribution to the efforts of the NIH Public Trust Initiative and other entities interested in alternative approaches and models to engage vulnerable communities in applied health research.
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