Grantee Research Project Results
2013 Progress Report: Endotoxin Exposure and Asthma in Children
EPA Grant Number: R834515Center: Denver Childrens Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Guo, Yanbing
Title: Endotoxin Exposure and Asthma in Children
Investigators: Schwartz, David A. , Covar, Ronina A , Litonjua, Augusto A. , Liu, Andrew H. , Murphy, Amy J , Strand, Mathew J. , Van Dyke, Michael V. , Martyny, John W. , Rabinovitch, Nathan
Institution: National Jewish Health
EPA Project Officer: Hahn, Intaek
Project Period: June 22, 2010 through June 21, 2015 (Extended to June 21, 2017)
Project Period Covered by this Report: June 22, 2013 through June 21,2014
Project Amount: $1,897,209
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
Project 1 – ENVIRONMENTAL EXPOSURE AND ASTHMA IN CHILDREN
We hypothesize that higher levels of endotoxin exposure cause persistent, problematic asthma and that key environmental (ozone and allergens) and genetic modifiers (endotoxin receptor polymorphisms) contribute to endotoxin susceptibility and pathological asthmatic responses. We are studying these endotoxin-induced airway conditions in children through three complementary clinical investigations.
First, we are capitalizing on an ancillary study of a NIH-sponsored multi-center cohort of children with asthma (Childhood Asthma Management Program), which has tracked asthma severity for over a decade, to determine if endotoxin exposure, modified by genetics and environment, is associated with greater disease severity and persistence.
Second, we are planning a panel study of children with asthma to investigate whether endotoxin exposure, modified by environment, is associated with inflamed airways and elevated TLR expression on airway macrophages. Clinically, these inflammatory responses could drive poor asthma control and exacerbations.
Finally, we are taking advantage of a HUD-sponsored inner-city home intervention study to determine if a home environment intervention will reduce home endotoxin levels and improve asthma. This combination of studies is expected to provide an understanding of how endotoxin interacts with other potentially toxic exposures in the susceptible host to cause persistent, problematic asthma. These studies will help us to determine the levels of endotoxin exposure that are likely to be problematic for children with asthma, and to develop environmental educational and intervention programs to improve health outcomes.
Project 2 – ENDOTOXIN DETERMINANTS OF EARLY HOST RESPONSE TO RSV
Project 3 – ENDOTOXIN DETERMINANTS OF EARLY HOST DEFENSE
The overall goal of this project is to understand how and why air pollution alters lung host defense. While the proposed research is focused on mice, we believe that the discoveries we make in mice will prove to be relevant to basic mechanisms of lung host defense in children. In fact, our findings in mice will be tested in Project 1 of this program. The environmental, clinical, and biological significance of this project is supported by the following observations. First, air pollution accounts for substantial morbidity and mortality throughout the world, including lung infections and preventable deaths in children. Second, endotoxin is ubiquitous in the environment and is associated with the development and progression of asthma and other forms of airway disease. However, the relationship between endotoxin and asthma is not simple since early childhood exposure to endotoxin, at least in certain populations, appears to protect children from developing asthma and atopy. Air pollution is contaminated with endotoxin, so this pathogen associated molecular pattern (PAMP) or other PAMPs may play a role in the pathophysiology of air pollution. Third, the ability of the host to respond to lipopolysaccharide (LPS; a specific form of endotoxin) and other PAMPs is highly variable in mice and humans, yet polymorphic host defense genes only account for a portion of this variable response. Fourth, innate immunity provides a first line of host defense against microbial pathogens that is conserved over a wide variety of species from flies to mammals. Indeed, innate immune signaling mechanisms in mice are almost identical to those in humans. Finally, the innate immune system is biologically dynamic and is responsive to both ozone and PAMPs. We have recently found that the expression of innate immune receptors on macrophages can be enhanced by ozone or PAMPs. Moreover, others have reported that some innate immune cells avoid excessive inflammation by selectively downregulating proinflammatory genes while continuing to transcribe antimicrobial genes. Thus, the overall hypothesis of this project is that the expression of toll-like receptors (TLRs) in the lung are influenced by environmental (ozone and/or PAMPs) and genetic factors, and the dynamic expression of TLRs has profound effects on lung host defense and, consequently, the development of lung infections and allergic airway disease.
Community Outreach and Translation Core (COTC)
The Community Outreach and Translation Core (COTC) forms a bidirectional bridge between researchers, community stakeholders, and community residents for:
• sharing thoughts, perceptions, information and needs;
• applying existing evidence; and
• informing and shaping future research that is responsive to the community.
A Community Advisory Board (CAB) serves as a forum for investigators, practitioners, and community stakeholders to discuss the activities of the Denver Children's Environmental Health Center (CEHC) and the priorities of the community. The CAB is composed of members of multi-disciplinary, multi-regional, and multi-sectoral stakeholders and serves as the direct link between investigators and the various communities in Colorado. The work of the COTC follows the principles of community based participatory research. CAB members are involved in the scientific process of the CEHC through a variety of means, including proposal review, question-and-answer sessions between CAB members and investigators, and CAB-led strategic planning meetings where community needs, potential targeted interventions, responsive research, and issues of feasibility are discussed. In addition, a central activity of the COTC is to work with community stakeholders and members to identify and share the key messages of the Center’s research findings, so that the community is able to take advantage of new discoveries.
Progress Summary:
During the fifth year of this Program Project in Environmental Asthma, substantial progress has taken place. All three independent projects and the three Cores have made excellent progress and have met all of their goals. The overall structure and necessary interactions within the Program is established, productive, and is insuring the continued success of the Program. Center investigators meet at least every month and scientific discussions and scientific collaborations between the investigators are naturally evolving. We are actively engaged in considering scientific options for our competitive renewal. In the following paragraphs, the highlights of the accomplishments of various components of the Program will be described.
Project 1 – ENVIRONMENTAL EXPOSURE AND ASTHMA IN CHILDREN
As proposed, 3 complementary studies address the aims and hypotheses of Project 1: (1) Childhood Asthma Management Program (CAMP) ancillary study; (2) Denver Asthma Panel Study (DAPS); and (3) Housing & Urban Development (HUD) ancillary study. Based on our CEHC’s research experience, progress and findings so far, we sought to strengthen the accuracy and relevance of our exposure assessments in DAPS by adding personal wearable exposure monitoring and bedroom air stationary monitoring. After EPA approval in January 2014, we successfully added and completed our Endotoxin Personal Exposure Monitoring Study (EPEM) to enhance, operationalize and validate our personal exposure monitoring for the longitudinal DAPS. Until recently, the lab assay for endotoxin has utilized limulus amebocyte lysate, a reagent that cross-reacts with molds. Now, there is an endotoxin assay based on recombinant Factor C, which only binds endotoxin. To advance scientific understanding of pure endotoxin exposure (i.e., independent of mold) and asthma outcomes, we developed and validated a Standard Operating Procedure to measure endotoxin using the rFC assay and established quality control parameters.
Our CAMP investigation is the first study, to our knowledge, to clearly distinguish household endotoxin from mold exposure in children with asthma. By using the endotoxin-specific rFC assay and separate mold exposure measures (i.e., mold plate counts), we evaluated the effects of household endotoxin and mold exposures on asthma severity. In fact, we found that higher endotoxin levels in baseline dust samples (n = 962) were associated with fewer prednisone days (an indicator of severe asthma exacerbations), while high mold counts were associated with more prednisone days during the 4-year course of the study. Only weak correlations were found between log mold concentrations and endotoxin levels (unadjusted r = 0.17; p = <0.0001). When the effects of endotoxin and mold exposures on prednisone days were assessed for each site (with both exposures in the model), endotoxin-associated reductions and mold-associated increases in prednisone days were found for 5 of the 8 CAMP sites (Baltimore, Denver, San Diego, St. Louis, and Toronto), consistent with the overall model.
We also investigated the interaction of endotoxin with 48 SNPs in 11 Toll-Like Receptor (TLR) genes (TLR-1, -2, -3, -4, -5, -6, -9, -10, CD14, MyD88, LY96, ACAA1) on severe asthma exacerbations (i.e., at least one ER visit or hospitalization for asthma in the past year). This preliminary analysis was restricted to CAMP participants of Caucasian ethnicity: 517 CAMP Caucasian participants included 84 cases with at least one severe asthma exacerbation vs. 433 controls. For two SNPs (in TLR9 and MyD88), the presence of the dominant genotype and higher endotoxin levels increase the risk of severe asthma exacerbations. Because of these significant TLR gene-endotoxin interactions, we expanded our genotyping of genes downstream of the TLR receptor complex. We also performed a genome-wide, pathway level analysis to develop a gene-byenvironment model for endotoxin exposure and asthma exacerbations. Glycosphingolipid metabolism showed the most evidence for interaction with endotoxin exposure at the pathway level (FDR < 0.04) in models of asthma severity. Gene polymorphisms that contributed to glycosphingolipid pathway enrichment included interaction of endotoxin with polymorphisms in SPTLC2, ASAH1, GALC, ARSB, PPAP2B and SPTLC1. Other pathways and functional groupings that showed possible interactions with environmental endotoxin were monoamine G protein coupled receptors (including muscarinic receptors (CHRM3), histamine receptors (HRH1)) (FDR = 0.06), the nitric oxide synthase pathway (FDR = 0.08), and Fc Epsilon Receptor 1 signaling in mast cells (FDR = 0.15). Pathway level analysis identified functional groupings of genes that may interact with ambient endotoxin exposure to alter asthma severity in children. These gene-by-environment interactions would not have been detected in a conventional genome wide survey of individual SNP-level gene-byenvironment associations.
For DAPS, as noted above, we strengthened the accuracy and relevance of our exposure assessments, by adding personal wearable exposure monitoring and bedroom air stationary monitoring. After EPA approval in January 2014, we successfully added and completed the Endotoxin Personal Exposure Monitoring Study (EPEM) to enhance, operationalize and validate personal exposure monitoring for DAPS.
In the EPEM study, we measured inner-city asthmatic children’s exposure to real-time PM10 (particulate matter<10μm), filter PM10, black carbon, and brown carbon using the MicroPEM™ (RTI International), and to NO2 using an Ogawa™ passive badge (Ogawa USA). Fifteen inner-city children (8-15 years) participated in this study. Eight participants reported exposure to cigarette smokers. Participants were instructed to wear personal monitors during waking hours. Stationary monitors (PEM™, MSP®) were installed into each participant’s bedroom. Targeted sampling period was 72 hours. Exposure levels between personal and stationary monitors were compared via linear mixed models with random intercepts for sibling pairs.
Waking wearing compliance (WWC) was excellent in 87% of participants, with a median WWC of 83% for those with acceptable WWC (>60%). Personal monitor levels were significantly higher than, and correlated variably with, stationary monitor levels for PM10 (>30% higher, p = 0.023; intraclass correlation coefficient (ICC) = 0.342, 95% confidence interval [-0.254; 0.399]), black carbon (>7-fold higher, p < 0.0001; ICC = 0.082[- 0.429;0.594]), and brown carbon (>4-fold higher, p<0.0001; ICC=0.635[0.166;1.103]). NO2 levels did not differ significantly. Based on the EPEM study, we conclude that accurate exposure assessment using personal exposure monitors, such as the MicroPEM™, are feasible for use with inner-city children. Stationary monitors inaccurately estimate personal exposure to PM, as they do not capture the higher concentrations found near strong PM emission sources. In contrast, in this cohort the main source of personal exposure to NO2 was detectable in their bedrooms. The EPEM analysis is in progress. We intend to analyze real-time PM10, endotoxin, fungal glucans, and possibly, allergens.
DAPS is a 1-year longitudinal investigation of children with asthma, to investigate airways inflammation, immunity, and TLR expression associated with endotoxin and ozone exposure, and their associations with asthma severity and exacerbations. We expect to determine if these exposures prime the airways for aberrant responses to respiratory viruses, leading to exacerbations. Relevant findings from our other Project 1 studies and our other Denver CEHC Projects were considered when developing this investigation in order to incorporate the most contemporary perspectives and hypotheses. Based on the experience and findings from the EPEM study, the DAPS protocol included EPEM exposure monitoring enhancements. DAPS participant enrollment began in July 2014, after IRB approval. As of September 9, 2014, 15 study participants were enrolled.
For the HUD study, 115 participants were enrolled, and the study participant follow-up visits were completed in March 2012. The HUD cohort comprised mostly ethnic minority children, with asthma, living in lowincome housing. The homes had many asthma triggers that were targets for remediation at three levels: Education Only, Minor Remediation, and Moderate Remediation. Endotoxin concentration was measured in 262 house dust samples collected from the general living area and participant’s bedroom. Seventy homes had all dust samples collected, meaning adequate dust samples for endotoxin measurement from both general living area and bedroom, before (Pre) and 6 months after (Post) remediation. Remediation did not significantly reduce house dust endotoxin levels measured 6 months later (Wilcoxon Rank Sums test).
Project 2 - ENDOTOXIN DETERMINANTS OF EARLY HOST RESPONSE TO RSV
This project has made substantial progress in achieving its overall objective to characterize the influence of postnatal ozone exposure on TLR expression and on airway structure and function. To the best of our knowledge, this is the first study to profile the transcriptome response of the newborn lung to acute ozone exposure using genome-wide gene expression microarray analysis. The results identified several novel genes and molecular pathways never before associated with ozone exposure. The pattern of gene expression and the molecular pathways perturbed by ozone in the newborn lung are different from those described previously for adult (fully developed) lungs. Specifically, it was mainly cell cycle-associated functions, including cell division/proliferation that were most altered significantly after acute ozone exposure in the developing newborn lung. It is not clear whether this suppression of the cell cycle/proliferation can lead to permanent damage to the lung (altered lung growth or altered structure and function) or if it is transient only, to allow repair of potentially damaged DNA from ozone exposure.
We also found that the airway response to ozone is age-dependent and this response is suppressed in the neonatal lung due to TLR-4 deficiency in this early age. The results also indicate that the neutrophilic airway response to ozone is dependent on TLR-4 signaling, whereas lung permeability is regulated by a mechanism independent of TLR-4 signaling. The role of neutrophils in ozone-mediated injury, whether pathogenic or protective, remains to be defined as planned in our future studies.
We have also focused on the effect of ozone on airway responsiveness to allergen exposure and RSV infection. Studies of the effects on allergen exposure showed that acute postnatal ozone exposure increased AHR but not airway inflammation or antibody response to subsequent exposure to house dust mite. We are repeating these studies to confirm the findings and to determine if the increased AHR is mediated through a neurogenic mechanism (e.g., via substance P-NK1 receptor pathway). Studies of the effects of postnatal ozone exposure on response to RSV infection are in progress and will determine if ozone alters innate or adaptive immunity to viral infection. Ozone is known to alter the defense mechanisms of the lung against bacterial infection, but its effects on respiratory viral infection are largely unknown. Therefore, we expect to obtain new information that will improve our understanding of the host response to viral infection during exposure to common air pollutants.
Project 3 – ENDOTOXIN DETERMINANTS OF EARLY HOST DEFENSE
We completed characterization of the effect of in vivo ozone exposure on lung innate immune response to Pam3CYS, a TLR2/TLR6 agonist. Ozone pre-exposure resulted in (1) increased whole lung lavage (WLL) cell influx, (2) increased IL-6 and KC, and decreased MIP-1α and TNF-α and (3) increased cell surface expression of TLR4, TLR2 and TLR1 on macrophages as a result of ozone alone or in combination with Pam3CYS. In addition, we demonstrated that ozone followed by Pam3CYS resulted in a large increase in phosphorylation of both p44/42 (Erk1/2) MAPK and JNK kinases and significant reduction in non-phosphorylated p44/42 MAPK at 4 hours post Pam3CYS. This enhanced signal associated with ozone/Pam3CYS treatment was not present at 24 hours. To further characterize the priming effect of ozone on innate immunity at the molecular level in an unbiased manner, we performed gene expression profiling on lung tissue of mice from the four exposure groups. Ozone exposure has the strongest effect on gene expression at the 4-hour time point with the effect diminishing by the 24-hour time point. Ozone pre-exposure prior to Pam3CYS treatment (O3/Pam3CYS vs. FA/Pam3CYS) enhanced induction of Trmt5 at the 4 hours and Cck at 24 hours. Expression of Ttk (4-hour time point), Pbp2, Gjb4, Ncapg, and Pbk (24-hour time point) were also increased in the O3/Pam3CYS vs. FA/Pam3CYS but significantly less than in the O3/saline vs. FA/saline comparison. The most significant result among downregulated genes is downregulation at 24 hours of killer cell lectin-like receptors (Klra3, Klra8, Klra9, Klra10, Klra15, Klra21, Klra22, Klra23, Klrb1a, and Klrk1). Our study demonstrates that expression of TLRs on macrophage surface is a dynamic process that is influenced by ozone and that this process is associated with differential expression of a number of previously unexplored genes. This dynamic nature of TLR expression is likely more general and could be influenced by other components of air pollution and in cell types other than macrophages. This priming effect of air pollution and genes that are associated with the process also represent potential therapeutic targets for air pollutant exposure in the context of pulmonary infection or allergic airway inflammation.
To understand how epigenetic mechanisms alter dendritic cell function and contribute to the etiology of allergic airway disease, we are developing a line of investigation that examines epigenetic marks and transcriptional profiles in distinct lineages of DCs that exist within the lung and recruited to the draining lymph nodes in response to allergic sensitization. Preliminary data demonstrate the approach we are taking to isolating these cells for epigenetic and gene expression studies.
To follow up on our published findings on the role of methyl donor diet in the development of allergic airway disease in mice, we compared allergic airway disease phenotypes between methylene-tetrahydrofolate reductase (MTHFR) deficient mice on a C57/Bl6 background to wild-type (WT) C57/Bl6 mice using a house dust mite (HDM) allergen model. In brief, mice received an intraperitoneal (i.p.) sensitization of 10μg HDM or saline on days 0 and 7 followed by an intratracheal (i.t.) challenge of 5μg HDM or saline on days 14 and 15. 48 hours after the final challenge, total cells and eosinophils in the bronchoalveolar lavage were 5.76 fold and 7.87 lower, respectively, in HDM-treated MTHFR deficient compared HDM-treated WT mice. Furthermore, HDM-treated MTHFR KO mice demonstrate a 1.64 fold (p < 0.05) reduction in lung resistance compared to HDM-treated WT mice in response to inhaled methacholine. These results suggest that allergic airway disease may be suppressed through the loss of MTHFR.
Community Outreach and Translation Core (COTC)
The COTC accomplished many activities to support achievement of our specific aims.
• Translation conference for community stakeholders (held June 11, 2013): All Center investigators presented their research to community stakeholders at the Air Quality Symposium: How does Air Quality affect health? This conference was extremely well attended (over 65 participants) by a variety of stakeholders including industrial hygienists, local and rural public health departments and school personnel. The presentations are also highlighted on our website (www.capk-12.org). The website holds many resources related to health and air quality for educators and the community.
• Three community fact sheets were developed: Particulate Matter, Pesticides and Ozone. They are available on the website and can be used in public health departments, health clinics, and as supplementation to class learning. The fact sheets were also provided to CAB members for use and further dissemination. The fact sheets have been used to supplement relevant lesson plans on our website to support K-12 educators. During the fire season in 2013, our brief on particulate matter served as the basis for an article in the Valley Courier (San Luis Valley) for community members to learn about particulate matter and how to protect themselves from the harms.
• CAPK-12 website (www.capk-12.org): This website provides environmental education related to air quality that is engaging and relevant to encourage youth and educators to become critical thinkers capable of making informed decisions and taking actions to improve air quality and health. We are working to continuously to update and review lesson plan packages. So far, the website has received over 5,000 unique visitors.
• EPA Environmental Educational Grants Sub-awards Program (September 2012- August 2014): To promote our Clean Air Projects and efforts to target children and youth through schools by integrating the environment and lung health using a critical thinking and problem-solving framework, we submitted and were awarded a grant to award sub-awards for environmental education efforts in EPA Region 8. In total, 19 projects received sub-awards reaching over 25,000 youth in EPA Region 8. More than fifteen lesson plans/resources were developed during the grant period. The funding also helped shape and enrich many classroom activities that will extend long-term and be sustainable beyond the grant period, mainly as a result of the passion and training of the educators involved in this program. The sub-awardees report substantial improvement in skills as environmental educators and have greater knowledge of resources and activities that are available to deepen the learning experience in the classroom. Nine public schools, three higher education institutions, and seven community organizations were funded to conduct a variety of activities in diverse settings.
• CAB meetings: The COTC hosted seven Community Advisory Board meetings. All Center investigators presented their research and dialogued with CAB members. CAB members provided updates on events and activities. Ms. Alicia Aalto retired from the Region 8 EPA office and stepped off the CAB; however, in her place Mr. Kyle Olson, from EPA Region 8, stepped in.
• Partnering with Community Organizations:
o San Luis Valley Ecosystem: Lisa Cicutto partnered with this community organization located in rural Southern Colorado to support a grant application that was successful. The San Luis Valley Ecosystem is the primary grant applicant/recipient. As part of the grant, she has worked with them to train school nurses and BSN nursing students about asthma and environmental triggers. The model is that the BSN students receive a class seminar (4 hrs) about asthma and environmental triggers and subsequently work with school nurses and implement Open Airways for Schools and case management for students with asthma or query asthma. Lisa Cicutto has worked with the team to organize a continuing educational session for health providers (including mental health, public health), school nurses and early childhood educators to learn about the effects of smoking (first hand, second hand and data for third hand smoking), counseling, resources and support services and smoking cessation programs. This 4 hour session was held on May 30.
o Denver Public Schools (DPS): Key messages from the interaction of COTC and CAB members are transferred back through educational programs provided by DPS Asthma program asthma counselors and Melanie Gleason, PA and Stanley Szefler, MD.
• Translation Activities: Our Center investigators and team members provided several presentations, seminars and consultations.
Future Activities:
The coming year will include DAPS visits and analyses and preparation of our findings for presentation and manuscript submissions. For the NIH-funded CAMP study, the Endotoxin Exposure Working Group completed its analyses, presented this work in 2014 at a premier meeting with special recognition by the AAAAI Environmental and Occupational Respiratory Diseases Interest Section, and is in the final stages of manuscript preparation for submission of their findings. We completed our collaborative investigation of endotoxin exposure and asthma outcomes in 150 inner-city children in Baltimore (NIH-funded MAACS Study: PI E. Matsui) and a manuscript of our findings was published. We also completed a collaborative investigation of endotoxin exposure and early childhood wheezing phenotypes in a Denver inner city pre-school cohort (NIH-funded CAPS Study: PI M.D. Klinnert). This was presented in 2014 at a premier meeting, and it is in the final stages of manuscript preparation for submission. We have submitted an abstract of our EPEM study for presentation in 2015 at a premier meeting. Additional EPEM analyses are ongoing. What we have learned from our CAMP, EPEM, MAACS, HUD and CAPS studies, and the other Projects and COTC in our CEHC is informing and strengthening DAPS, the longitudinal study that is ongoing in Year 5 of this award.
The COTC’s objective for the next year is to develop and disseminate community educational resources identified as priority areas by community stakeholders. In addition, CAB members and Center investigators will work together to translate and disseminate the results of Center studies to community.
Journal Articles: 31 Displayed | Download in RIS Format
Other center views: | All 51 publications | 30 publications in selected types | All 30 journal articles |
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Alper S, Warg LA, De Arras L, Flatley BR, Davidson EJ, Adams J, Smith K, Wohlford-Lenane CL, McCray Jr PB, Pedersen BS, Schwartz DA, Yang IV. Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria. Genetics 2016;204(1):327-336. |
R834515 (Final) |
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Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies:the Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. |
R834515 (Final) R835436 (2017) R836159 (2018) |
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Das R, Subrahmanyan L, Yang IV, van Duin D, Levy R, Piecychna M, Leng L, Montgomery RR, Shaw A, Schwartz DA, Bucala R. Functional polymorphisms in the gene encoding macrophage migration inhibitory factor are associated with gram-negative bacteremia in older adults. Journal of Infectious Diseases 2014;209(5):764-768. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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De Arras L, Seng A, Lackford B, Keikhaee MR, Bowerman B, Freedman JH, Schwartz DA, Alper S. An evolutionarily conserved innate immunity protein interaction network. Journal of Biological Chemistry 2013;288(3):1967-1978. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Gabehart K, Correll KA, Yang J, Collins ML, Loader JE, Leach S, White CW, Dakhama A. Transcriptome profiling of the newborn mouse lung response to acute ozone exposure. Toxicological Sciences 2014;138(1):175-190. |
R834515 (2011) R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C002 (2015) R834515C003 (2014) |
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Gabehart K, Correll KA, Loader JE, White CW, Dakhama A. The lung response to ozone is determined by age and is partially dependent on toll-like receptor 4. Respiratory Research 2015;16:117. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C002 (2015) R834515C003 (2014) |
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Gao Z, Dosman JA, Rennie DC, Schwartz DA, Yang IV, Beach J, Senthilselvan A. NOS3 polymorphism, lung function, and exposure in swine operations: results of 2 studies. Journal of Allergy and Clinical Immunology 2014;134(2):485-488. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Henao-Martinez AF, Agler AH, LaFlamme D, Schwartz DA, Yang IV. Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea bacteremia. Infection, Genetics and Evolution 2013;16:386-391. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Jing J, Yang IV, Hui L, Patel JA, Evans CM, Prikeris R, Kobzik L, O'Connor BP, Schwartz DA. Role of macrophage receptor with collagenous structure in innate immune tolerance. Journal of Immunology 2013;190(12):6360-6367. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Kelada SN, Wilson MS, Tavarez U, Kubalanza K, Borate B, Whitehead GS, Maruoka S, Roy MG, Olive M, Carpenter DE, Brass DM, Wynn TA, Cook DN, Evans CM, Schwartz DA, Collins FS. Strain-dependent genomic factors affect allergen-induced airway hyperresponsiveness in mice. American Journal of Respiratory Cell and Molecular Biology 2011;45(4):817-824. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C003 (2014) R834515C003 (2016) |
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Lai PS, Hofmann O, Baron RM, Cernadas M, Meng QR, Bresler HS, Brass DM, Yang IV, Schwartz DA, Christiani DC, Hide W. Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin. PLoS One 2013;8(5):e62910. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Long H, O'Connor BP, Zemans RL, Zhou X, Yang IV, Schwartz DA. The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One 2014;9(4):e93550 (10 pp.). |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Matsui EC, Hansel NN, Aloe C, Schiltz AM, Peng RD, Rabinovitch N, Ong MJ, Williams DL, Breysse PN, Diette GB, Liu AH. Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children. American Journal of Respiratory and Critical Care Medicine 2013;188(10):1210-1215. |
R834515 (2012) R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C001 (2015) R834515C002 (2014) R834515C003 (2014) R834510 (2014) |
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Oakes JL, O'Connor BP, Warg LA, Burton R, Hock A, Loader J, LaFlamme D, Jing J, Hui L, Schwartz DA, Yang IV. Ozone enhances pulmonary innate immune response to a Toll-like receptor-2 agonist. American Journal of Respiratory Cell and Molecular Biology 2013;48(1):27-34. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Szefler SJ, Dakhama A. New insights into asthma pathogenesis and treatment. Current Opinion in Immunology 2011;23(6):801-807. |
R834515 (2011) R834515 (Final) |
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Szefler SJ. Advancing asthma care: the glass is only half full! Journal of Allergy and Clinical Immunology 2011;128(3):485-494. |
R834515 (2011) R834515 (Final) |
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Szefler SJ. Advances in pediatric asthma in 2011: moving forward. Journal of Allergy and Clinical Immunology 2012;129(1):60-68. |
R834515 (2011) R834515 (Final) |
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Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;303(5):L391-L400. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012; 303(5):L391-L400.. |
R834515 (Final) |
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Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;303(5):L391-L400. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Yang IV, Alper S, Lackford B, Rutledge H, Warg LA, Burch LH, Schwartz DA. Novel regulators of the systemic response to lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology 2011;45(2):393-402. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
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Yang IV, Tomfohr J, Singh J, Foss CM, Marshall HE, Que LG, McElvania-Tekippe E, Florence S, Sundy JS, Schwartz DA. The clinical and environmental determinants of airway transcriptional profiles in allergic asthma. American Journal of Respiratory and Critical Care Medicine 2012;185(6):620-627. |
R834515 (Final) |
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Julian CG, Yang IV, Browne VA, Vargas E, Rodriguez C, Pedersen BS, Moore LG, Schwartz DA. Inhibition of peroxisome proliferator-activated receptor gamma: a potential link between chronic maternal hypoxia and impaired fetal growth. FASEB Journal 2014;28(3):1268-1279. |
R834515 (Final) |
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Kelada SN, Carpenter DE, Aylor DL, Chines P, Rutledge H, Chesler EJ, Churchill GA, Pardo-Manuel de Villena F, Schwartz DA, Collins FS. Integrative genetic analysis of allergic inflammation in the murine lung. American Journal of Respiratory Cell and Molecular Biology 2014;51(3):436-445. |
R834515 (Final) |
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Liang L, Willis-Owen SAG, Laprise C, Wong KCC, Davies GA, Hudson TJ, Binia A, Hopkin JM, Yang IV, Grundberg E, Busche S, Hudson M, Ronnblom L, Pastinen TM, Schwartz DA, Lathrop GM, Moffatt MF, Cookson W. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature 2015;520(7549):670-674. |
R834515 (Final) |
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Eyring KR, Pedersen BS, Yang IV, Schwartz DA. In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome. PloS one 2015;10(12):e0144087 (10 pp.). |
R834515 (Final) |
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Julian CG, Pedersen BS, Salmon CS, Yang IV, Gonzales M, Vargas E, Moore LG, Schwartz DA. Unique DNA Methylation Patterns in Offspring of Hypertensive Pregnancy. Clinical and Translational Science 2015;8(6):740-745. |
R834515 (Final) |
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Yang IV, Pedersen BS, Liu A, O’Connor GT, Teach SJ, Kattan M, Misiak RT, Gruchalla R, Steinbach SF, Szefler SJ, Gill MA, Calatroni A, David G, Hennessy CE, Davidson EJ, Zhang W, Gergen P, Togias A, Busse WW, Schwartz DA. DNA methylation and childhood asthma in the inner city. Journal of Allergy and Clinical Immunology 2015;136(1):69-80. |
R834515 (Final) |
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Lai PS, Liang L, Cibas ES, Liu AH, Gold DR, Baccarelli A, Phipatanakul W. Alternate methods of nasal epithelial cell sampling for airway genomic studies. Journal of Allergy and Clinical Immunology 2015;136(4):1120-1123.e4. |
R834515 (Final) |
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Yang IV, Richards A, Davidson EJ, Stevens AD, Kolakowski CA, Martin RJ, Schwartz DA. The nasal methylome: a key to understanding allergic asthma. American Journal of Respiratory and Critical Care Medicine 2017;195(6):829-831. |
R834515 (Final) |
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Yang IV, Pedersen BS, Liu AH, O'Connor GT, Pillai D, Kattan M, Misiak RT, Gruchalla R, Szefler SJ, Khurana Hershey GK, Kercsmar C, Richards A, Stevens AD, Kolakowski CA, Makhija M, Sorkness CA, Krouse RZ, Visness C, Davidson EJ, Hennessy CE, Martin RJ, Togias A, Busse WW, Schwartz DA. The nasal methylome and childhood atopic asthma. Journal of Allergy and Clinical Immunology 2017;139(5):1478-1488. |
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Supplemental Keywords:
Endotoxin, exposure, children, asthma, risk, health effects, susceptibility, sensitive populations, genetic pre-disposition, genetic polymorphism, indoor air, dose-response, ozone, remediation, human health, asthma indices, intervention, RFA, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Allergens/Asthma, Health Effects, Children's Health, Biology, asthma, asthma triggers, sensitive populations, endotoxin, asthma indices, airway inflammation, children, allergic responseRelevant Websites:
Project 1: Endotoxin Exposure and Asthma in Children - See more at: https://www.nationaljewish.org/professionals/research/programs-depts/center-for-genes-environment-and-health/research/childrens-environmental-health/project-1#sthash.7OZwN1BK.dpuf Exit
Progress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834515C001 Endotoxin Exposure and Asthma in Children
R834515C002 Environmental Determinants of Early Host Response to RSV
R834515C003 Environmental Determinants of Host Defense
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2015 Progress Report
- 2014 Progress Report
- 2012 Progress Report
- 2011 Progress Report
- 2010 Progress Report
- Original Abstract
30 journal articles for this center