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Record Count: 17
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DESCRIPTION (provided by applicant): The homozygous NQO1*2 polymorphism results in a total lack of NQO1 activity due to accelerated degradation of the mutant NQO1*2 protein by the ubiquitin/proteasomal pathway. The NQO1*2 polymorphism has been found to be a risk factor for benzene-induced myeloid toxicity but also for childhood and adult de-novo leukemias and secondary leukemias arising as a result of chemotherapy. The mechanisms underlying the protective effects of NQO1 against benzene-induced myelotoxicity and both de-novo and secondary leukemias were puzzling since NQO1 was not expressed in aspirated human bone marrow cells or human bone marrow CD34+ progenitor cells, the target cell for induction of both aplastic anemia and leukemia. However, we observed that NQO1 was present in human bone marrow endothelial cells (HBMEC), which are not harvested by bone marrow aspiration. In the present application, we wish to explore the potential role of NQO1 in HBMEC in protection against benzene induced aplastic anemia and have established HBMEC cultures in our lab for this purpose. We propose a mechanism whereby HBMEC exposed to benzene metabolites produce increasing amounts of endothelial IL8 (elL8) which results in apoptosis of neighboring hematopoietic cells and myeloid progenitor cells resulting in aplastic anemia. We will also examine the mechanism underlying the lack of expression of NQO1 in human myeloid cells at the transcriptional level by characterizing cis acting DNA sequences and trans acting nuclear protein-DNA interactions that modulate NQO1 expression. One of the major tumor suppressor genes characterized in mammalian systems is p53 and a high percentage of leukemias contain mutations or allelic losses of p53. In preliminary data, we demonstrate that NQO1 forms a protein complex with wild type p53. We propose to examine whether the interaction of NQO1 and p53 is specific for wild type p53 and whether it has consequences for p53 stability and p53-dependent transcriptional activation of downstream genes. If NQO1 stabilizes p53 and the interaction has functional consequences, this would provide a mechanism for the increased incidence of leukemia of diverse origin that has been associated with a lack of NQO1 protein due to the NQO1*2 polymorphism.
DESCRIPTION (provided by applicant): In USA, at least 4% of full term boys are cryptorchid. This is one component of a testicular dysgenesis syndrome (TDS). TDS originates during fetal development, but frequently is first detected years later as testicular cancer, defective spermatogenesis, and cysts/adenomas of the excurrent ducts. Testicular cancer, the most common potentially malignant tumor in young men, is 3-11X more likely in those born cryptorchid. Our long-term goal is to delineate molecular mechanisms underlying cryptorchidism and transformation of testicular cells into precancerous cells. Cryptorchidism can be inherited, but in humans no individual gene alteration is associated with >5% of cases. There is increasing acceptance that endocrine disrupter agents (EDAs) frequently are causative for cryptorchidism and predispose for testicular cancer. Understanding how EDAs act epigenetically to block expressions of genes for testicular descent has been hampered by low prevalence of non-experimental cryptorchidism. This project overcomes that obstacle. We propose study of a population of Sitka Black-Tailed Deer (SBTD) on the Aliulik Peninsula of Kodiak Island, AK, documented to have 76% cryptorchidism (91% bilateral, BCO). This population is not genetically different from unaffected populations in other locales. We hypothesize that: (1) this extraordinarily high incidence of cryptorchidism in SBTD is due to in utero exposure of fetuses to an estrogenic EDA which alters expression of genes crucial in testicular programming and descent; and (2) TDS syndrome in SBTD will mimic that in humans, making results translatable to humans. Specific Aims are: Aim 1. Genes and Gene Expression in SBTD. Study gene expression and protein accumulation in samples of testes and gubernacular remnants from BCO and non- cryptorchid (NCO) adults. Initial focus on genes for InsIS and LGR8/Great; then AR plus ERa. Compare sequences of genes dysregulated in BCO deer with those in NCO deer to detect genetic mutations. Microsatellite DNA analyses will characterize each animal's genetic background. Aim 2. Estrogenic molecules in SBTD and potential EDA vectors. Direct chemical analysis might detect and quantify culprit estrogenic EDA, if any, affecting gene expression. Assay with MCF-7 cells should detect action of estrogenic EDA and, hence, allow characterization of epigenetic dysregulation of InsIS, Great, AR, and/or ER genes after exposure to EDA. Results will clarify the interaction of genetics and EDAs as cause of cryptorchidism.
DESCRIPTION (provided by the applicant): Immune-mediated adverse drug reactions (IADR) are unpredictable and can be life-threatening. Although current studies suggest that IADR are caused by immunogenic drug-protein adducts, it remains unclear why these reactions are restricted to susceptible groups of patients. The objective of the present proposal is to test the hypotheses that Kupffer cells (KG) are incompetent antigen presenting cells (APC) that intrinsically cause T cell tolerance, and that impairment of the tolerogenic function of KC may be a key factor that modulates immune reactions against protein adducts and significantly affects susceptibility to IADR. The specific aims of the proposed studies will be to determine the following: 1. The roles of inadequate expression of co-stimulatory molecules and production of IL-10 in the mechanisms of KC-induced T cell tolerance. The capability of KC to induce T cell activation will be compared with that of potent APCs, such as splenic dendritic cells and peritoneal exudate macrophages. The role of inadequate expression of co-stimulatory molecules in KC-induced T cell anergy will be determined in vivo and in vitro. Further, the capacity of KC to produce IL-10 and the role of IL-10 in KC-mediated T cell tolerance will be investigated.
2. Whether "danger signals" may convert KC from tolerogenic to immunogenic APC. Evidence suggests that an increased risk of IADR in susceptible individuals may be linked to concurrent infection and/or inflammation, in which "danger signals", may be generated to stimulate the immune system. Thus, it is our hypothesis that tolerogenic KC may be converted to potent immunogenic APC by "danger signals", thereby, leading to an increased propensity toward developing IADR. This hypothesis will be examined using two widely recognized "danger signals": lipopolysaccharides and heat shock proteins. 3. Whether KC plays an important role in inducing immunological tolerance against protein adducts derived from a therapeutic agent that causes IADR. A model hapten was used in the preliminary studies to demonstrate the tolerogenic effects of KC. However, it is important to further investigate whether the immunosuppressive effects of KC may be extended to a therapeutic agent that causes IADR. This hypothesis will be examined using halothane, which is known to cause allergic hepatitis with clinical features consistent to IADR.
DESCRIPTION (provided by applicant): Chronic intoxication with manganese (Mn) is the cause of a degenerative movement disorder, termed manganism, with clinical features that resemble Parkinson's disease. Recent findings suggest that injury to this region of the brain involves perturbation of the normally supportive function of glial cells to an activated state that results in increased expression of inflammatory genes such as inducible nitric oxide synthase (NOS2), that can subsequently produce neurotoxic levels of nitric oxide (NO). Similar deleterious neuro-glial interactions occur in other degenerative disorders of the basal ganglia, such as Parkinson's and Huntington's diseases, highlighting the need to elucidate the mechanisms underlying these damaging interactions. The long-term goal of this research program is to better understand role of glial cells in the pathogenesis of diseases of the basal ganglia. The objective of this application is to identify mechanisms underlying glial-mediated neuronal injury in an experimental model of manganism. The central hypothesis is that Mn exposure results in glial activation and expression of NOS2 that contributes to age-dependent neuronal injury and debilitation of basal ganglia function through overproduction of NO. This hypothesis will be tested by pursuing two specific aims: 1) Determine the Mn-dependent signals that cause induction of NOS2 in astroglial cells. The working hypothesis for this aim is that Mn increases NF-KappaB-dependent expression of NOS2 by activating specific MAP kinases. 2) Identify the mechanisms underlying age-dependent susceptibility of the basal ganglia to manganese. It is postulated under this aim that Mn-mediated production of NO during development results in glial activation and neuronal injury that decreases the threshold for basal ganglia dysfunction upon subsequent exposures. The experimental approach proposed utilizes genetic interdiction of specific signaling molecules in the NF-KappaB pathway to identify critical upstream activators of NOS2 expression in astroglial cells. The activity of the factors identified will be quantified in relation to activity of NF-KappaB and expression of NOS2 in neonatal and adult wildtype and transgenic mice exposed to Mn. It is expected that this innovative approach will identify important early targets of Mn that promote neuronal injury by increased synthesis of NO. The proposed research is significant, because it is expected to advance understanding of the pathogenic role of glial-derived NO in disorders of the basal ganglia and, thereby, to foster the development of neuroprotective therapeutic strategies that target inflammatory signaling pathways in glial cells.
DESCRIPTION (provided by applicant): Oxidant air pollutants like ozone increase risk for exacerbation of cystic fibrosis, asthma, and COPD. Ultrafine particulates, which also can bear surface free radicals, can have such effects, alone or in synergy with ozone. Oxidant gases like supraphysiologic oxygen and ozone cause extracellular ATP release from lung cells, activating critical survival signals. Prompt, reversible ATP release due to ozone (50-200 ppb) occurs in tracheal, bronchial, small airway, and alveolar epithelial cells, appears due to calcium-, rho kinase-, and PI 3-kinase-dependent vesicular exocytosis, and, in polarized bronchial epithelium, is mainly from the apical surface. Acute ozone exposure also causes ATP release into lung epithelial lining fluid in mice within 15 min. In vitro, enzymatic removal of extracellular ATP increases cell death, while ATP, DTP, or a nonhydrolyzable ATP analog prevent ozone-induced apoptosis and necrosis. The protecting agonists, and their inhibition by P2 and P2Y receptor-specific antagonists, indicate a role for P2Y receptors. Extracellular ATP activates ERK 1/2 and Akt signaling. Besides epithelial injury, ozone causes release of cytokines like interleukin-8 (IL-8). IL-8 appears in CF airways even before bacterial infection, being the earliest identified pathologic event. We hypothesize that extracellular ATP preserves epithelial energy metabolism, airway cell survival and inhibits IL-8 release due to ozone in normals, that impaired ATP release in CF airways causes opposite effects, and that supplemental extracellular ATP or similar agonists will reverse these processes in CF and normals. Our specific aims are: (1) measure ATP release, IL-8 release, and cell death in CF and non-CF airway human epithelium in response to ozone, (2) quantitate ozone-mediated ATP release, inflammatory cytokine release, and cell injury/death in airways of CFTR- mutant and non-mutant mice, (3) assess effects of ATP, DTP and ATP analog supplementation in CF and non-CF airway epithelium in ozone in vitro and in vivo, and determine activated signaling pathways and related metabolic effects. Polarized monolayers of primary and transformed CF-mutant and normal airway epithelium cultured on permeable supports with an air-liquid interface will be used. These studies will increase our understanding of lung oxidant injury and repair in CF and normals, and of normal defense mechanisms of airway epithelium.
DESCRIPTION (provided by applicant)
It is well recognized that in the United States asthma morbidity and mortality are increased in urban poor minority populations where increased exposures to outdoor and indoor particulate occur. The specific aim of this study to assess the interactions between expression of common polymorphisms related to airway inflammation and health effects associated with particulate exposures among children with asthma. The investigators hope to define the interaction between expression of these polymorphisms and biological and health effects associated with particulate in a cohort of urban-poor predominantly minority children with mild to severe asthma who attend the Kunsberg School on the campus of National Jewish Hospital.
Forty-five children who are students at the Kunsberg School will be followed on a daily basis over 4 consecutive school years beginning October 2007. Urine leukotriene E4 levels will be collected from each child on 16 consecutive schooldays and exhaled nitric oxide will be sampled as a marker of airway inflammation. Hourly ambient fine particulate concentrations will be monitored and personal exposure monitoring of particulate will be performed. Children will be assessed for expression of the glutathione-s-transferase m-1 and the 5-lipoxygenase tandem repeat polymorphisms. As these children attend school daily, the Kunsberg School provides a unique population in which individual exposures and asthma severity indices can be measured daily while other potentially confounding triggers can be monitored concurrently. In this way the interaction between genetic variability and environmental exposures can be precisely measured in children with asthma.
Beryllium sensitization and chronic beryllium disease (CBD) continue to affect individuals who have occupational or environmental exposure, especially those with genetic susceptibility. The long-term objectives of this Program Project Grant are to evaluate the basic immune and inflammatory mechanisms underlying beryllium sensitization and chronic beryllium disease, and to establish the relationship between beryllium exposure and immunogenetics. The proposal consists of four projects and three core units. Project 1 will determine the mechanisms by which beryllium induces aberrant, high production of the pro- inflammatory cytokine tumor necrosis factor-alpha in CBD, focusing on the priming effects of interferon-gamma and direct effects of beryllium sensitization, in the progression from sensitization to CBD, and in the development of severe forms of this granulomatous disorder. Project 3 will determine the role of beryllium-reactive CD4+ T cells and the affinity of the T cell antigen receptor for the beryllium/peptide/major histocompatibility (MHC) complex. In doing so, this project will determine qualitative and quantitative differences in T cell recognition of beryllium, in the ability of beryllium-specific CD4+ T cells to secrete pro-inflammatory cytokines, utilizing this information to develop biomarkers of disease progression. Project 4 will determine the role of oxidative stress in enhancing the antigen presenting cell's ability to present beryllium antigen to T cells. It will test the hypothesis that beryllium induces oxidative stress which promotes an excessive cytokine response and T cell proliferation in CBD. The overall rationale for the Program Project is to use an interdisciplinary approach to define the genetic underpinnings of the cellular response to beryllium, to relative mechanisms to human exposure risk factors, and develop new biological markers of CBD risk, disease progression, and prognosis.
DESCRIPTION (provided by applicant): This Small Business Technology Transfer Phase I project will develop a prototype online perchlorate monitor for a resin bed perchlorate remediation reactor. The device will be have less than 4 ppb limit- of-detection, provide results in less than 3 min., and require only periodic microchip replacement as routine maintenance. Currently, perchlorate can only be detected below 10 ppb using laboratory based equipment requiring trained technicians and, most importantly, at least several hours of time, and therefore, impractical for online monitoring. The Henry Group at Colorado State University has recently demonstrated sub ppb perchlorate detection using a patent-pending lab-on-a-chip technology with results that include real water sample testing. This technology opens the door for online monitoring of perchlorate remediation operations, which will significantly reduce the costs. Entire resin beds costing $100k in materials and additional costs in disposal would no longer be needed. This Phase I proposal will: 1. Develop pumps, valves, instrumentation, etc. to assemble a field deployable device, 2. Optimize our microchip functions by incorporating a sample membrane barrier and assessing nonhazardous alternative internal standards, and 3. Method validation and field testing. PUBLIC HEALTH RELEVANCE: Human exposure to perchlorate is of concern because of the potential for impaired thyroid function, leading to a number of developmental delays and other medical problems. Its prevalence in the environment only gained interest in the late 1990's, once a method was developed for its detection at the 4 ppb level. In 2005 after being added to the Environmental Protection Agency's (EPA) Unregulated Contaminant Monitoring Rule (UCMR1) list, a sampling of 2800 large water systems and 800 smaller systems, representing less than 10% of all US water systems, revealed contamination in 153 sites over 25 states. As of 2005, 120 remediation projects were underway, including 15 superfund sites, costing hundred's of millions of dollars to fund, mostly coming from government coffers. Our online monitoring device will significantly reduce costs for remediation. In addition to lowering costs to existing remediation, it will also allow smaller communities address cleanup that would otherwise not have enough resources.
DESCRIPTION (provided by applicant): No ozone monitors exist today that are small enough, sensitive enough, and selective enough for widespread use in detecting and tracking low part-per-billion (ppb) levels of ozone that can be used for detailed research of the health effects of human exposure to low-ppb concentrations ozone, particularly for sensitive individuals such as asthmatics, children, and the elderly. Improved ozone sensors are needed in order to make reliable in-field exposure measurements for individuals with asthma and other respiratory diseases. Improved understanding of the impacts of environmental toxins, such as ozone, on public health can eventually result in increased protections for at-risk individuals. Synkera Technologies is proposing the development and validation of a new, credit-card sized device that will be able to detect low levels of ozone (<12 ppb) in real-time with the required spatial resolution in order to aid research on respiratory diseases. This sensor will build upon recent advances in electrochemical sensing technology to create a next generation product that is significantly smaller, faster, more sensitive, stable and lower cost than any electrochemical sensor available today. The novel sensor will be a solid-state electrochemical device, based on existing nanotechnology expertise available at Synkera, with a form factor that will allow for integration into small monitors Phase I will demonstrate the feasibility of the approach by fabricating and extensively testing prototype sensors. Proof-of-concept will be established if we are able to demonstrate the feasibility of detection of low ppb ozone levels (~10 ppb) with sufficient selectivity and stability. In Phase II the ozone sensors will be optimized, electronics to operate the sensors will be developed, prototype monitors will be produced, and field trials will be performed. PUBLIC HEALTH RELEVANCE: The development of a wearable, easy to use, point-of-contact ozone monitor will allow for widespread population studies to further explore the affects of environmental exposure on respiratory incidents and respiratory disease. Such a device will support programs like the NIH- wide Genes and Environment Initiative (GEI), which seeks to identify major genetic susceptibility factors for diseases of public health significance and develop technology for measurement of potential causative environmental exposures. This type of research and development will provide significant information regarding health disparities that may lead to differential health outcomes.
DESCRIPTION (provided by applicant): The goal of this Phase II program is develop, test and produce a prototype field analytical instrument for electrochemical monitoring of arsenic in drinking water. This program seeks to provide a new avenue to laboratory-quality arsenic detection and quantification in a field-portable device at reasonable cost. The long term vision for this technology is that it will become a key environmental science tool to support the development of strategies to prevent arsenic-related disease in individuals and population and to help people liver longer, healthier lives, a key aspect of the mission of NIEHS. We envision this technology also having a role in the international arsenic contamination picture, particularly in countries such as Bangladesh, where over 70% of drinking water wells contain toxic concentrations of arsenic. Specific Aims of the Phase II program will include design and construction of a prototype field-portable analytical system for detection of arsenic in drinking water at concentrations between sub-ppb and many ppm. The performance of the instrument will be characterized in the lab for the effects of real sample issues, including several classes of interferences and environmental variables. Once fully characterized, the prototype will be tested in the field with selected stakeholders in the drinking water distribution system arena. The new prototype technology will be benchmarked against standard analytical laboratory methods and other available field tests, such as colorimetric kits. During Phase I, favorable comparison to standard analytical laboratory analysis has already been obtained on drinking water samples from New Mexico and remediation treatment process water from Nevada. These results provide high confidence that the proposed analytical methodology will be an effective tool to prevent arsenic related disease from drinking water exposure. In the United States and globally, contamination of drinking water by naturally occurring arsenic puts populations at risk of a variety of arsenic-related diseases. The proposed Phase II program will provide a cost- effective and highly accurate way to monitor arsenic in drinking water at the site of the water source. The long- term vision for this technology is that it will become a useful tool for helping to arsenic-related disease among exposed populations.
DESCRIPTION (provided by applicant): This three-phase Small Business Innovation Research project addresses one the most significant problems in public health protection: monitoring of indoor air quality and controlling the ventilation systems in residential, office and industrial buildings. The development of a novel advanced microsensor for detecting gaseous formaldehyde in air is proposed. The sensing method utilizes the conductivity change induced, upon exposure to formaldehyde, in a layer of tin oxide. Cross-sensitivity to other volatile organic chemicals is eliminated by patterning of the tin oxide surface by an inert protecting layer with sub-nanometer pores, each shaped to selectively host a single formaldehyde molecule. Incorporation of this novel sensing material into a high-area nanostructured sensor platform will enable production of highly sensitive, selective, low-power, and low-cost formaldehyde microsensors. The Phase I project will demonstrate the feasibility of the proposed approach through fabrication of sensors and their comprehensive testing in conditions simulating contaminated indoor air. To ensure successful Phase II product development and Phase III commercialization, partnership has been secured with one of the leading developers of components and systems for energy applications. By combining coordination chemistry with nanotechnology and microfabrication, the proposed approach is likely to enable a novel family of low-cost highly sensitive and selective sensor systems for precise quantitative monitoring of human exposures to toxicants. Thus, the proposed research is highly relevant to the mission of the National Institute Of Environmental Health Sciences.
Public Health Relevance: The project addresses one the most significant problems in public health protection: monitoring of indoor air quality and controlling the ventilation systems in residential, office, and industrial buildings. The development of novel advanced sensors for detecting formaldehyde - one of the most ubiquitous and dangerous for human health air contaminants - is proposed. The proposed technology will enable a novel family of high-performance and low-cost sensor systems for generating precise and quantitative measures of human exposure to harmful chemicals at the point of contact.
DESCRIPTION (provided by applicant): In this proposal we respond to the call by the National Institute of Environmental Health Sciences (NIEHS) in the PHS 2007-2 Omnibus Solicitation for "new products/devices, tools, assays to improve our ability to precisely measure environmental exposures to individuals with high temporal and spatial resolution." According to the solicitation, the device should be of appropriate scale to be field deployable and/or wearable. Ozone, formed in photochemical air pollution, has well documented adverse effects on human health, including reduction of lung function and aggravation of preexisting respiratory disease such as asthma. Emergency department visits, daily hospital admissions and mortality increase during episodes of high ozone concentration. A Personal Ozone Monitor (POM) is required for environmental health studies of the physiological effects of ozone and for validating computer models of human exposure such as the Air Pollution Exposure (APEX) model used by the Environmental Protection Agency to assist in establishing national air quality standards. We propose to develop a small (4 x 3 x 1 inch), light weight (d 1 lb), low power (d 3 watts), low cost (d $800 in parts) battery-operated POM based on the well established method of UV absorbance. The instrument will result from further miniaturization of a backpack-sized instrument already commercialized by 2B Technologies and successfully tested as a personal exposure monitor. The pocket-sized POM will have a precision and accuracy of better than 2 ppb and make new measurements every 10 s. The instrument will have an internal data logger and USB computer interface for downloading data into a personal computer. During Phase I, we will evaluate and select miniaturized components, design and construct a prototype POM, test the prototype for effects of orientation, vibration and rapid temperature and humidity change, and, finally, characterize the instrument with respect to the analytical figures of merit of linearity, precision and accuracy. PUBLIC HEALTH RELEVANCE: A pocket-sized, battery powered Personal Ozone Monitor (POM) will be developed and tested. The POM, which will be based on the well established method of UV absorbance, will facilitate physiological studies of the adverse effects of ozone, formed in air pollution, on human health.
DESCRIPTION (provided by applicant)
The candidate, Dr. Arthur Mayeno, is applying for a K25 Mentored Quantitative Research Career Development Award, in hope of achieving his long-term goal of becoming an independent researcher in quantitative and computational modeling of biological systems. After earning a Ph.D. in organic chemistry and working in the pharmaceutical industry for several years as an analytical chemist, he wishes to transition back into academic research and apply his knowledge and experience in chemistry toward biomedical research. Professor Raymond Yang, in the Department of Environmental and Radiological Health Sciences at Colorado State University, has agreed to be his mentor. Both he and the Department are committed to helping Dr. Mayeno achieve his goals by providing guidance, support, and the research environment. Dr. Mayeno has proposed a career development plan tailored to his needs that include coursework, participation at meetings and workshops, training in the responsible conduct of research, limited teaching, and research in a relevant area of computational toxicology. The proposed research centers on modeling the biotransformation of polychlorinated biphenyls (PCBs), a family of 209 related chemicals, which are ubiquitous environmental pollutants. Although it is known that PCBs and their metabolites exert biological and toxic effects on humans and other organisms, the underlying mechanism behind these health effects remains unclear due, in part, to the complexity of the biochemical interactions involved. A successful model should permit the study and simulation of the metabolism of complex PCB mixtures more representative of the true exposure, and more importantly, provide insight into the underlying molecular basis for the toxicology of PCBs. The proposal herein represents just the first step in developing a comprehensive model and will focus on modeling the biotransformation of PCBs by a single relevant cytochrome P450 (CYP) isozyme, CYP1A1. The research will be accomplished via the following specific aims: In specific aim 1, quantitative structure-reactivity correlations (QSRCs) will be determined that correlate the molecular parameters of a PCB with its rate of metabolism and the site(s) of reaction within the PCB molecule. In addition, a database of "reaction rules" describing the reactions catalyzed by CYP1A1 will be developed to represent the biotransformation pathways. In specific aim 2, the QSRCs and reaction rules will be used to create reaction network models for PCB metabolism. Finally, in specific aim 3, the model(s) will be refined and validated.
DESCRIPTION (provided by applicant):
The candidate's overall career goal is to become a leading, independent researcher in the field of air pollution and air pollution effects on public health. Career objectives related to this grant are to: a) enhance the candidate's knowledge of pulmonary biochemistry and physiology, b) develop technical expertise in cellular toxicology, and c) develop an independent research program that integrates the fields of mechanistic toxicology with air pollution physics and exposure assessment. The long term goal of this research is to establish mechanistic, dose-response relationships between inhaled air pollutants and lung disease. Merging the fields of in vitro toxicology and exposure assessment is a necessary step in realizing this goal. Therefore, the immediate objective is to develop a realistic, physiological model for air pollutant deposition in vitro. The investigator's model will accomplish this task by approximating particle size-specific deposition patterns of particulate aerosols to pulmonary epithelial cells housed within a state-of-the-art in vitro lung model. This model will be developed, calibrated, and finally validated against the existing state-of-the-art model.
In vitro toxicology can be employed as a relatively low-cost, rapid screening method for elucidating these mechanisms across many cell types. Establishing a link between exposure and health effect 1) provides a means for further innovations in the prevention and treatment of pulmonary disease, specifically allowing for more targeted (and resource-intensive) in vivo experimentation to follow from in vitro screening tests, 2) allows for intervention and control strategies targeted to reduce specific toxic components of ambient air pollution, and 3) helps provide the necessary information for regulating agencies to set more protective, health-based standards.
Description (provided by applicant): Sulfur mustard (HD, mustard gas) is the most highly utilized chemical weapon in history, and currently it poses a serious threat to both military and civilian populations. In addition to stockpiles, HD remains one of the easiest chemical weapons to make in large quantities, and it is included in the list of likely choices for terrorist organizations. HD can be a severely debilitating agent for those exposed to it. The primary organs affected by HD are the lungs, skin and eyes. It results in acute airway edema, ARDS, bronchopneumonia, tracheobronchomalacia and/or airway stenosis, bronchiolitis obliterans, bronchiectasis, pulmonary fibrosis, asthma, and other respiratory complications. There are no specific treatments or antidotes for HD nor preventive medications to minimize its effects. Decontamination and supportive care are the only interventions recommended by current medical guidelines and more of these protect the airways. Decontamination is effective for skin and eyes only if enacted very early (< 5 minutes). Unfortunately, recognition of the problem usually does not occur within this timeframe. We hypothesize that supplementation or augmentation of airway mono- or dithiols will prevent or limit sulfur mustard toxicity. Using an animal model employing 2-chloroethyl ethyl sulfide (CEES, "half-mustard"), a less toxic analog of sulfur mustard, we will: 1) Determine airway inflammation, pro-inflammatory cytokines, and principal thiols following half-mustard aerosolization in rat, 2) evaluate effectiveness of oral and aerosolized mono- (GSH) and dithiols (lipoic acid, thioredoxin) in attenuating halfmustard lung injury (inflammation, cytokines, thiols), 3) develop novel compounds to stimulate mono- and dithiol efflux into lung epithelial lining fluid, and 4) examine the efficacy of these novel compounds in vivo. The latter studies will help us establish optimal compounds, route and mode of delivery, pharmacokinetics, bioavailability, and toxicology. Our laboratories have exceptional experience in measurement of the relevant, potentially protective thiol compounds to be evaluated. We anticipate these studies will lead to testing of the most effective compounds using authentic mustard gas at appropriate facilities.
DESCRIPTION (provided by applicant): This proposal is to request support for a Keystone Symposia meeting entitled "Frontiers in Reproductive Biology and Regulation of Fertility", organized by Sudhansu K. Dey, Martin M. Matzuk and Kelle H. Moley, which will be held in Santa Fe, New Mexico from February 1 - 6, 2009. Sexual reproduction is a complex and highly regulated process essential for successful propagation and diversification of genetic complements, beginning with germ cell development and completing with birth of live young. For successful reproduction, a plethora of events including gametogenesis, ovulation, fertilization, implantation, and placentation requires precise regulation; the success of each go-ahead event is dependent on the accomplishment of the preceding event. Research on these events and their coordination has been translated into clinical practice, particularly for enhancing successes in fertility clinics, controlling gynecological diseases and developing contraceptives. This meeting is designed to bring together a diverse group of leaders, established and rising in the field, who study the complex regulation of reproduction and related developmental processes. The speakers and participants will comprise a group that uses a variety of model systems to better understand the processes relevant to human and animal reproduction and fertility regulation. The meeting will focus on stages critical to reproductive success, beginning with germ cell renewal and differentiation and ending with the biology of placentation. The first areas covered are reproductive tract morphogenesis and testicular biology. The focus will then turn to preimplantation biology, with topics including energy metabolism in embryos and early cell lineage specification. Emphasis will also be placed on the importance of communication between various tissue signaling pathways, including germ cell-somatic cell dialogue, cross-talk between the corpus luteum and deciduum, and the symbiotic relationship between the embryo and uterus. In light of the continued use of hormone therapy for fertility regulation and exposure to environmental toxicants and endocrine disruptors, a session is included to highlight epigenetic, environmental and hormonal impacts on various aspects of reproductive events. The emerging concepts regarding potential roles for noncoding RNAs, stem cells and imprinting during reproduction will also be discussed, particularly their relevance to embryo development, attachment and placentation.
Project Narrative: The principal goal of this conference is to stimulate cross-disciplinary exchange and integration of information concerning reproduction, which will allow attendees to identify the current problems that most significantly impact human reproductive health and the routes for ameliorating or curing these conditions.
DESCRIPTION (provided by applicant)
This proposal is to request support for a Keystone Symposia meeting entitled "Epigenetics, Development and Human Disease", organized by Anne Ferguson-Smith and Steven Henikoff, which will be held in Breckenridge, Colorado from January 5-10, 2009. This meeting aims to provide a stimulating forum for exploring the epigenetic control of genome function illustrated through the regulation of a variety of biological processes in a range of model organisms. The role of factors influencing chromatin organization and chromosome architecture, and the dynamic changes in the epigenetic state that regulate development, are two well-established but fast-moving areas that will be covered. The dynamic nature of epigenetic states renders them both adaptable and vulnerable; this will be explored in sessions considering the influence of the environment on epigenetic control, and the causes and consequences of epigenetic change in disease. The investigators anticipate that the data presented will allow evolutionary insights and functional comparison of epigenetic mechanisms in different organisms and systems, resulting in the integration of ideas to generate new concepts and a deeper understanding in this field.
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