2004 — 2006 |
Van Winkle, Laura S |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Prenatal Tobacco Smoke and Expression in Airways @ University of California Davis
DESCRIPTION (provided by applicant): Metabolism is a key step in eliminating xenobiotics from the body. Despite the fundamental importance of metabolism in determining the potency of contaminants and carcinogens, little is known about the influence of exposures early in life on the adult expression of these systems, particularly in females. Environmental tobacco smoke (ETS) is one of the most ubiquitous sources of pulmonary exposure to known human carcinogens. Widespread exposure of children to ETS is supported by the fact that as many as 85% of children have detectable levels of cotinine in their blood. Yet the effect of early life exposure on adult onset lung diseases such as cancer has received limited attention. We propose to investigate the effect of pre and post-natal ETS exposures on the expression of genes for metabolism and detoxification enzymes in the target organ for airborne carcinogens, the lung. ETS toxicity is of interest in the female population because women develop lung cancer earlier and after less cigarette exposure than men. We propose to investigate female specific alterations in gene expression in the airways. We will examine the effects of ETS exposures on the lung by comparing the gene expression profiles and histopathology of samples obtained from female mice exposed to well characterized aged and diluted side stream tobacco smoke with those from filtered air control mice. The proposed studies will use microarray approaches to define, at the cellular level, the occurrence and persistence of altered gene expression in mice exposed either prenatally or both pre and postnatally to side stream cigarette smoke. We will use an experimental approach that identifies changes in genes as well as pathobiology specific to conducting airways, the site of many changes associated with both smoke exposure and adult onset diseases such as asthma, chronic bronchitis and lung cancer. The central hypothesis is that adult onset lung diseases in females, such as lung cancer and asthma, are related to the ability of the lung to metabolically activate compounds and this is profoundly influenced by the history of prior exposure to such compounds, particularly in utero. We will address the central hypothesis through 3 Specific Aims that will define: 1) the effect of pre and postnatal ETS exposure on gene expression in adult airways, 2) the effect of prenatal ETS exposure on gene expression in infant airways and 3) which changes in infant gene expression persist into adulthood. These studies will thus address the fetal basis of adult diseases of the lung caused by exposure in utero to environmental tobacco smoke.
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1 |
2005 — 2008 |
Van Winkle, Laura S |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gonadal Vs. Genomic Influences On Xenobiotic Metabolism @ University of California Davis
DESCRIPTION (provided by applicant): Metabolism is a key step in eliminating xenobiotics from the body. Despite the fundamental importance of metabolism in determining the potency of contaminants and carcinogens, little is known about sex-specific differences in critical metabolic pathways. Differences between the sexes can be due to steroid hormone (gonadal) interactions or to differences in gene content (genomic interactions). We propose to investigate the effect of gonadal vs. genomic interactions on metabolism of a class of ubiquitous environmental contaminants (polycyclic aromatic hydrocarbons, PAHs) in a primary target organ for chemical carcinogenesis, the lung. The model compound will be naphthalene, the predominant PAH in environmental tobacco smoke and a byproduct of fossil fuel combustion. Human exposure to naphthalene is a concern as naphthalene was recently declared a likely human carcinogen. Naphthalene toxicity is of interest in the female population for 3 reasons: 1) women develop lung cancer earlier and after less cigarette exposure than men, 2) naphthalene causes lung tumors in female (but not male) mice and 3) data shows that female mice are more sensitive than male mice to naphthalene pulmonary toxicity. Sex-specific effects on metabolism and detoxification of naphthalene in the lung will be investigated in this proposal. Alterations in these systems may pre-dispose the lungs of females to increased airway epithelial injury and subsequent remodeling dependent on the stage of the reproductive cycle at which exposure occurs. The central hypothesis is that elevated susceptibility of females to metabolically activated compounds, such as naphthalene, is influenced primarily by gonadal hormones. The central hypothesis is addressed through two specific aims. These will determine if: 1) Female gonadal hormones regulate pulmonary metabolism of naphthalene and 2) Female-specific gene expression regulates pulmonary metabolism of naphthalene. We will use a multidisciplinary approach that combines morphology, site-specific quantitative gene expression, enzyme activity measures and proteomic approaches to define the effect of sex and steroid hormones on bioactivation of naphthalene. The proposed studies are relevant to diseases associated with pulmonary remodeling and PAH activation, such as lung cancer.
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1 |
2008 |
Van Winkle, Laura S |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Acquisition of Lmd6000 Laser Microdissection Unit @ University of California Davis
[unreadable] DESCRIPTION (provided by applicant): The instrument requested is a Leica LMD6000 Multi-user Laser Capture Microdissection Microscope System. We are requesting the multi-user configuration of this equipment because it has the capability to capture tissues and cells for proteomics, genetics, and live cell subcloning; features that are required by our user group. The other laser capture systems currently available on campus are not sufficient for the projects described because they 1) are too slow, 2) cannot do large areas of tissue quickly, 3) require expensive technical support and are highly scheduled already, 4) cannot cut hard tissues such as plants, embryos or decalcified bone. The Leica LMD6000 differs significantly from other laser capture units primarily in the mechanism of sample capture as well as speed and ease of use; a major advantage for a multi-user piece of equipment requiring high throughput. The new equipment is needed to advance the research programs of 15 investigators on the UC Davis campus. Many of these investigators are already collaborators; 11 are members of an NIEHS Center for Environmental Health Sciences and 5 are co-investigators on an NIEHS Program project, in addition to their individual funding sources. The users represent a broad range of scientific interest on campus in College of Biosciences (2), School of Medicine (4), School of Veterinary Medicine (6), and College of Agriculture and Environmental Sciences (3). The research is highly focused on both basic sciences and human health and includes studies of inhalation toxicology of air pollutants, animal models of asthma, stem cell repair in the lung, cell fate patterning in plant and mammalian embryos and in seminiferous tubules, heart disease, fertility and reproduction, general toxicology, inflammation, breast cancer metastases, dioxin effects on pancreas and kidney and keratinocyte function/toxicity. All the proposals have one common element, the need for laser dissection to quickly analyze complex composites of cells either in culture or in tissues. Outreach to other campus users will be facilitated by maintaining the equipment in a core facility, listing on the CEHS Center's website, and by mentioning the equipment in Dr. Van Winkle's graduate course. The overall benefits to the UC Davis campus are many. This equipment fits well with the research needs of the UC Davis community, which has included a recent emphasis on genomics. [unreadable] [unreadable] [unreadable]
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1 |
2010 |
Van Winkle, Laura S |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Acquisition of a Leica Tcs Lsi Zoom Confocal Microscope @ University of California At Davis
DESCRIPTION (provided by applicant): The instrument requested is a Leica TCS LSI zoom confocal microscope system. We are requesting the current configuration because it has the greatest flexibility in capability and can capture images from live tissues and cells as well as image very large fields of view. The other confocal systems currently available on campus are not sufficient for the projects described because they 1) are too slow, 2) cannot image large fields of view without stitching, 3) are highly scheduled already, 4) are not the correct configuration for our user needs being primarily inverted micrscopes with small working distances and 5) do not have an environmental chamber for imaging large live specimens. There is not currently available on this campus any truly comparable confocal microscope in terms of capability. Hence this microscope will enable studies that were not previously possible or were only achievable in a substandard way with a tremendous investment of both money and time. The Leica TCS LSI differs significantly from other confocals primarily in the ability to image large fields of view and to zoom from low to high magnification. The software is easy to use and the image capture is high resolution and very fast;a major advantage for a multi-user piece of equipment requiring high throughput. The new equipment is needed to advance the research programs of 14 investigators on the UC Davis campus. The users represent a broad range of scientific interest and span four schools/colleges on campus (Medicine, Veterinary Medicine, Agriculture and Environmental Sciences and Engineering). The research is highly focused on both basic sciences and human health and includes studies of inhalation toxicology of air pollutants, animal models of asthma, studies of the circulatory system including heart/vascular disease, brain and nervous system dysfunction, stem cell repopulation of airways and whole animal studies of medaka fish. All the proposals have one common element, the need for a microscope with a large field of view and high resolution to analyze complex composites of cells either in culture or in tissues, quickly. Placement of this equipment in core facilities at UC Davis will also facilitate the projects of graduate students, postdoctoral fellows, residents and professional school (DVM or MD) researchers. Outreach to other campus users will be facilitated by maintaining the equipment in a core facility, listing the equipment on the core and center websites and by inclusion in Dr. Van Winkle's teaching in campus courses on imaging. The overall benefits to the UC Davis campus are many. This equipment fits well with the research needs of the UC Davis community, which has included a recent emphasis on the childhood health disorders autism and asthma that require large field imaging capability for neurons and airways respectively.
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1 |
2012 — 2013 |
Van Winkle, Laura S |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Prenatal Bisphenol a and Lung Maturation @ University of California At Davis
DESCRIPTION (provided by applicant): More than 90% of all US urine samples tested contain detectable levels of bisphenol A (BPA) indicating widespread and continuous exposure. BPA exposure affects specific life stages with early pre or neonatal exposure to low dose of BPA resulting in organizational changes in the prostate, breast, testis, mammary glands of laboratory animals. The effect of fetal BPA exposures on lung development, particularly of airways which are critical for asthma pathogenesis, has not been studied. Airway diseases such as asthma develop in early childhood and have undergone a perplexing increase in prevalence in the latter half of the 20th century. There is some evidence for a link between BPA exposures and asthma, maternal exposure to BPA in mice increases hallmarks of asthma in offspring. The goal of this application is to define how fetal BPA exposure changes secretory product maturation in the conducting airways of the lung. The central hypothesis is that BPA exposure alters mucous cell and Clara cell distribution and abundance in the conducting airways, a well as their principle secretory products. The central hypothesis is supported by our preliminary data which shows more abundant airway epithelial mucosubstances in the conducting airways and increases in gene expression of MUC5B and CCSP in the fetal rhesus monkey lung exposed to BPA. We will address the central hypothesis with two specific aims that will use site-specific lung morphometry and a mouse model of BPA-induced airways hyperresponsiveness to define: 1) the effect of fetal BPA exposure on airway epithelial secretory cell maturation and 2) whether altered distribution and abundance of secretory cells and their protein products persists in the postnatal period. Completion of the research aims will advance our understanding of normal secretory cell and secretory product maturation in the prenatal period in two species, mice and rhesus macaques. Understanding of the effect of BPA on the airway will aid in understanding of how BPA may exacerbate respiratory diseases characterized by abnormal airway secretions and how this subsequently can contribute to airways hyperresponsiveness. The proposed studies use two animal models to investigate BPA effects. These studies could not be conducted in children. This will advance our understanding of the potential relationship of BPA exposure to airway diseases characterized by elevated mucin secretions, such as asthma, the most common chronic condition of childhood.
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1 |
2013 — 2021 |
Ding, Xinxin [⬀] Van Winkle, Laura S |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Metabolic Mechanisms of Naphthalene Toxicity in Lung
Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. NA causes nasal and lung toxicities, including tumors, in adult rats and mice and has been classified as a possible human carcinogen. The mechanism of NA carcinogenicity, which may involve both genotoxic and non-genotoxic events, is not clear. A prerequisite for NA cytotoxicity is bioactivation by cytochrome P450 (CYP) enzymes. The reactive metabolites formed, which derive from the NA-epoxide (NAO), can deplete cellular glutathione and bind covalently to proteins. Research in the current funding cycle, which was focused on NA bioactivation and acute lung toxicity, provided compelling evidence for the ability of human CYP2A13 and 2F1 to mediate NA?s lung toxicity in vivo in a humanized mouse model, and insights on the interplay between systemic disposition and target tissue bioactivation of inhaled NA and its impact on NA?s airway toxicity. Initial novel evidence was also obtained for the ability of NA to produce stable DNA adducts ex vivo, and for a possible role of systemically generated NA metabolites in lung toxicity in vivo. In the proposed studies for the next funding cycle, we will continue to study the metabolic mechanisms of NA lung toxicity by: identifying liver-generated NA metabolites that contribute to lung toxicity in vivo (Aim 1), determining the ability of human CYP2A6 expressed in the mouse liver to mediate airway toxicity of inhaled NA (Aim 2), and identifying the stable NA- DNA adducts in the lung and dissecting metabolic mechanisms of their formation (Aim 3). The central hypothesis is that NA has the potential to cause both cytotoxicity and genotoxicity in human lung, and that the metabolism of NA in both lung and liver influences the toxic outcome on an individual basis. We will employ a combination of in vivo, ex vivo, and in vitro approaches, and utilize novel genetically modified or humanized mouse models, as well as human lung cells and liver microsomes, to address the specific aims. The long- term goal of these studies is to define the metabolic mechanisms that influence NA-mediated lung toxicity in experimental animals and humans. The outcome is expected to improve assessment of human lung disease risks from exposures to NA and other related chemicals.
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0.964 |
2015 — 2019 |
Van Winkle, Laura S |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Pilot Projects Program @ University of California At Davis
Abstract - Pilot Projects Program The overall goal of the Pilot Project Program (PPP) is to expand the UC Davis research base in environmental health sciences (EHS) and to attract new or established investigators to turn their attention to environmental health problems. The PPP will promote EHS research through provision of research funding, promotion of Core resource usage, and intellectual support. Research funds are expected to jumpstart new research endeavors focused on environmental health, through feasibility investigation, collection of preliminary data, establishment of proof of principle or small studies that are consistent with the broad mission and scientific themes of the EHS Core Center, and especially with translational potential, and to hold promise of generating new resources. This Program will emphasize support for junior investigators, as well as those investigators new to environmental health or exploring substantially new research directions and whose research brings an innovative viewpoint to the study of environmental health with relevance to human conditions. Available funds for the PPP were greatly enhanced through partnerships with seven other programs, centers and departments. The PPP process involves: 1) issuing a request for proposals, 2) reviewing pre-proposals, 3) referring applicants to Facility Core Design Clinics for guidance, 4) finding reviewers, and 5) reviewing proposals both scientific and programmatic merit, with final funding decisions made by the Center Leadership Group. The PPP's specific objectives are to: (a) provide support for junior investigators to develop a research program in EHS; (b) facilitate exploration of innovative new directions that can measurably advance EHS research; (c) develop resources, approaches, or technology that benefits EHS research for multiple center members; (d) promote interdisciplinary research; and (e) promote community engagement and translational research. The significance of this is underscored by the need to support and promote the careers of junior faculty as well as to expand research that employs conceptual or technological innovations in environmental health sciences of benefit to the broader EHS community and other Center scientists.
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1 |
2016 — 2020 |
Pinkerton, Kent Ed [⬀] Thomasy, Sara Michelle Van Winkle, Laura S |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Respiratory and Ocular Toxicity of Inhaled Nanomaterials @ University of California At Davis
SUMMARY We hypothesize differences in composition, size, diameter and surface coating of engineered nanomaterials (ENM) will modulate the in vivo deposition, distribution and biologic effects of aerosolized ENM to the lungs and the eyes. In this project, we will systematically test diverse ENM following aerosolization to identify the key characteristics that influence their toxicity. We have chosen to examine health effects in the respiratory tract and the eye, since both organ systems represent the major route of exposure to aerosolized ENM. Our focus will be to create real and relevant exposure scenarios by inhalation to the major classes of ENMs, a common and expected route of exposure. Further, the lungs and the eyes are both current targets of ENM-based therapeutic delivery. Our goal in this proposal is to systematically and quantitatively compare the health effects of nanomaterials with different physicochemical properties on these organ systems using physiologically relevant models. The health effects will include detailed molecular and pathophysiologic changes that will be targeted to zones of ENM deposition and retention. We are well positioned to contribute to the new NHIR consortium efforts on ENM. We have experience working with many of the materials listed. Because a potentially large number of materials will be systematically tested, a tiered paradigm with clear indications for which ENM need in vivo testing will be used. We have a strong publication record of ENM health effects research in vivo and ex vivo, particularly of novel material aerosols including laboratory generated, dry powder and nebulized liquid aerosols. Our team has expertise in metals, metal oxides, carbon particles, carbon nanotubes and 3-dimensional ENM Coupled with this are the novel methods developed in the Van Winkle, Thomasy and Pinkerton laboratories to study site-specific cellular responses and well-characterized methods in corneal and retinal imaging commonly used in physician-based ophthalmology. These novel approaches include microscopic and histologic approaches to localize ENM in tissues as well as the application of microdissection to study ENM retention and site specific gene, protein and cellular responses. Further, all three investigators have the ability to take advantage of a unique resource, the California National Primate Research Center This enables in vitro studies of ENM effects in a model physiologically relevant to humans, nonhuman primate explants and cells. We know that cell lines give divergent results and so the proposed studies in this application will emphasize primary cells or tissue explants for our organs of interest, coupled with in vivo studies of select ENM aerosols as defined by the consortium. The specific aims of our proposal provide novel and innovative methods to measure cell-based cytotoxicity, inflammation and remodeling in both normal and injury repair models of the complete respiratory tract, as well as the cornea and retina.
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1 |
2017 |
Van Winkle, Laura S |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Acquisition of a Cytoviva Hyperspectral Microscopy System @ University of California At Davis
ABSTRACT Darkfield imaging enables detection of unlabeled materials in tissues. The system we are requesting, a CytoViva Hyperspectral Microscopy system, combines proprietary darkfield microscope optics with hyperspectral detection to allow imaging, mapping and characterization of nanoscale materials (particles, viruses, bacteria) in tissues and cells. Darkfield imaging that is coupled with hyperspectral imaging, allows verification of the object through a characteristic spectral profile. The proprietary condenser increases the resolution over standard darkfield. The hyperspectral aspect of this system can also be used to understand histologic staining co- localization. Over the past 10 years, the UC Davis Cellular and Molecular Imaging Core (CAMI) has combined excellence in microscopy and fluorescence with complete sample preparation capabilities to serve over 90 UC Davis user laboratories. This is an established, shared facility resource that is supported with a fee for use (re-charge). The capabilities of the CytoViva system are needed by the co-investigators on this application. These major and minor users will use this instrument to study how nanomaterials interact with tissues and cells, to monitor bioavailability and composition of nanotherapeutics, to study the biology of inflammatory cells and to understand subtle shifts in toxicologic pathology and pathogen responses. This instrument does not duplicate existing instrumentation on our campus. Additional capability that will be supplied with this instrument includes fluorescence to allow colocalization of fluorescent signals with the hyperspectral image as is required by our users. The robust image analysis software included with this system allows spectral identification of nanoscale objects in a wide range of environments based on wavelength, scatter intensity, and scatter spatial properties. Most importantly, the image analysis software enables identification of nanoscale objects in the spectral image based on peak wavelength allowing standard histologic approaches to be used. This provides an important intermediate analysis capability as an alternative to EM or Raman spectroscopy for sample analysis and offers significant benefits to users in terms of lower cost and faster throughput. CAMI staff will provide training and consulting on imaging projects involving the CytoViva system and placement of this instrument in our core facility is a logical complement to our current capabilities which include excellence in sample preparation. This equipment will increase the impact of NIH funded research at UC Davis.
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1 |
2019 — 2020 |
Van Winkle, Laura S |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Postnatal Ozone and Altered Lung Growth @ University of California At Davis
Abstract Over 50% of the US population, more than 162 million people, live with unhealthy levels of ozone. This includes 38 million children. Ozone disrupts lung development, changes lung structure, and exacerbates respiratory disease. Reduced lung functional growth has been found in young adults with histories of ozone exposure as children. Our central hypothesis is that ozone-induced lung remodeling during lung development interacts with other air pollution exposures, such as particulate matter, to contribute to lung disease in adulthood. This R21 is a key initial step towards our long term goal of addressing this hypothesis in a subsequent larger application. Our goal in this application is to establish the extent of ozone-induced distal lung alteration, identify key mechanisms of ozone altered lung growth and to demonstrate the effect of these structural changes on deposition and clearance of a model inhaled ultrafine tracer particle. We will use unique animal, exposure and measurement methods we developed to address existing research gaps about ozone effects on airway and alveolar remodeling. In particular we will define target and nontarget regions of ozone induced lung remodeling and will study the mechanisms of the ozone induced cellular changes including glutathione depletion. We will use juvenile and adult, male and female rats exposed to ozone or filtered air (FA) in 2 Specific Aims that will: 1) Define changes in distal lung structure induced by ozone exposure and 2) Quantify the effect of ozone induced distal lung remodeling on particle deposition and clearance in the lung. A better understanding of the mechanisms and effects of distal lung remodeling in response to ozone exposure during lung development and reduced lung function in adulthood will support regulations that improve human health and will aid in designing therapies to treat ozone-reduced lung function.
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1 |
2020 — 2021 |
Van Winkle, Laura S |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Pilot Project Program @ University of California At Davis
PROJECT SUMMARY ? Pilot Projects Program The overall goal of the Pilot Project Program (PPP) is to expand the UC Davis research base in environmental health sciences (EHS) and to attract new or established investigators to turn their attention to environmental health problems. The PPP will promote EHS research through provision of research funding, promotion of Core resource usage, intellectual support and integration within the Center as well as with other programs at UC Davis. Research funds are expected to jumpstart new research endeavors focused on environmental health, through feasibility investigation, collection of preliminary data, establishment of proof of principle or small studies that are consistent with the broad mission and scientific themes of the Environmental Health Sciences Core Center (EHSCC), and especially with translational potential, and to hold promise of generating new resources. This Program will emphasize support for junior investigators, as well as those investigators new to environmental health or exploring substantially new research directions and whose research brings an innovative viewpoint to the study of environmental health with relevance to human conditions. Support will also be provided to established EHS researchers exploring new directions. Available funds for the PPP were, and continue to be, greatly enhanced through partnerships with other programs, centers and departments. The PPP process involves: 1) issuing a request for proposals, 2) reviewing pre- proposals, 3) referring applicants to Facility Core Design Clinics for guidance, 4) finding reviewers, and 5) reviewing proposals for both scientific and programmatic merit, with final funding decisions made by the Center Leadership Group and Stakeholder Representative. The PPP?s specific objectives are to: (a) provide support for junior investigators and/or established researchers new to EHS to develop a research program in EHS; (b) facilitate exploration of innovative new directions to advance EHS research; (c) develop resources, approaches, or technology that benefit EHS research for multiple center members; (d) promote interdisciplinary research; and (e) promote community engagement and translational research. The significance of this is underscored by the need to support and promote the careers of junior faculty as well as to expand research that employs conceptual or technological innovations or that has translational benefit for community stakeholders.
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1 |
2021 |
Van Winkle, Laura S |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Advanced Training in Environmental Health Sciences @ University of California At Davis
PROJECT SUMMARY This is a competing renewal application for a highly successful T32 program that has trained more than 180 predoctoral students in toxicology/environmental health sciences (EHS) over the last 45 years. The objective of this predoctoral program is to train the next generation of environmental health scientists through interdisciplinary research and coursework that address issues of direct relevance to the NIEHS mission. We are requesting 2 years of support for each of 8 predoctoral trainees beginning after their first or second year in a PhD degree program. Trainees are recruited from several UC Davis graduate programs that provide disciplinary training relevant to EHS, including toxicology, cell and molecular biology, exposure assessment, epidemiology, neuroscience, immunology and genetics. Training faculty ? 32 active researchers from 19 departments ? have substantial experience mentoring predoctoral students. Faculty research focuses on mechanisms by which environmental factors contribute to human disease and encompasses diverse areas within EHS, including respiratory toxicology, cancer, neurotoxicology, genotoxicity, epigenetics, and metabolic disorders. Significant interactions between training faculty members promote interdisciplinary approaches to EHS research. Trainees have access to advanced technologies, such as proteomics, epi/genomics and metabolomics, state-of-the-art imaging, genetically modified organisms, and inhalation facilities for rodents and non-human primates. A strength of EHS research at UC Davis is the vertical integration of studies directed toward understanding environmentally induced disease. Molecular, cellular, tissue, and diverse animal models, including nonhuman primate models, complement human clinical samples obtained through the UC Davis Clinical and Translational Science Center (CTSC) and epidemiologic studies. The training program leverages the activities and resources of multiple research centers at UC Davis to provide synergy and promote connections to disease prevention and public health; examples include the NIEHS P30 Environmental Health Sciences Core Center at UC Davis, the MIND Institute, Center for Children's Environmental Health, NCI Comprehensive Cancer Center, Western Center for Agricultural Health and Safety, NIEHS Superfund Program and the NIEHS Center for Nanotechnology Health Implications Research. The training program emphasizes practical instruction in scientific writing and communication of scientific findings to peers and lay audiences through chalk talks, annual retreats, town halls, and national meetings. Trainees are also exposed to emerging concepts, controversies, and technologies in environmental health by participating in a trainee-organized and -managed seminar series that hosts leading environmental health scientists from across the country, as well as through faculty?student interactions during a summer course in which trainees explore a current issue relevant to environmental health under the guidance of training faculty. Trainees will receive training in responsible conduct of research. The training program builds on an excellent track record of training leaders in EHS in academia, government, and the private sector.
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1 |
2021 |
Bein, Keith (co-PI) [⬀] Lein, Pamela J [⬀] Van Winkle, Laura S |
RF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
Traffic-Related Air Pollution Exacerbates Ad-Relevant Phenotypes in a Genetically Susceptible Rat Model Via Neuroinflammatory Mechanism(S) @ University of California At Davis
Project Summary Alzheimer?s disease (AD) is the most prevalent age-related neurodegenerative disease in the United States. More than 90% of cases are idiopathic and there is growing consensus that gene x environment interactions influence the age of onset and progression of this devastating disease. Epidemiological studies have reported a positive correlation between exposure to traffic-related air pollution (TRAP) and the occurrence of the hallmark clinical characteristics of AD. Preclinical studies support a causal relationship between TRAP and increased AD risk, but many of these studies used concentrated ambient particles or diesel exhaust that do not recapitulate the complexity of current real-world TRAP exposures. We have designed a unique exposure model in which TgF344-AD rats expressing human AD susceptibility genes are exposed in real-time to TRAP collected from a major freeway tunnel system, which preserves the gaseous and particulate components of real-world TRAP and captures daily fluctuations in pollutant levels. We will leverage this model to test our central hypothesis that TRAP decreases the time to onset and/or increases severity of AD-like phenotypes via microglial cell activation secondary to lung inflammation by addressing the following specific aims: (1) Determine which vehicle emission component(s) cause neuroinflammation and neurodegeneration in the TgF344-AD rat; and (2) Investigate the role of the lung-brain axis in mediating TRAP effects on AD phenotypes in the genetically susceptible TgF344-AD rat. In Aim 1, male and female TgF344-AD rats will be transported to the tunnel vivarium at 1 month of age and then exposed to gases, particulate matter (PM), or both from light duty only vs. light and heavy-duty vehicle exhaust. Outcomes including blood brain barrier (BBB) integrity, particulate matter in the brain, microglial and astroglial activation, AD-relevant pathology, lung pathology, and spatiotemporal profiles of soluble inflammatory mediators and immune cells in the lung, blood, and brain, will be assessed at 4, 9, 12, and 15 months of age. In Aim 2, we will assess the contributions of pulmonary inflammation and microglial activation to TRAP effects on AD by quantifying AD phenotypes in TRAP-exposed male and female TGF344-AD rats fed chow supplemented with pirfenidone or Senicapoc, which block pulmonary fibrosis via inhibition of TGF-? signaling or inhibition of KCa3.1 ion channels, respectively. Outcomes, which include cognitive behavior plus the endpoints measured in Aim 1, will be assessed at 12 and 15 months of age. Our broad long-term objectives are to inform regulatory and health interventions aimed at reducing AD risk for individuals living, working, or attending school near busy roadways.
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1 |