| Survey Results of HHS and HHS-Sponsored Research on the Health Effects of Exposure to Indoor Mold |
| National Institutes of Health (NIH) Survey Results |
| Ongoing Research as of October 1, 2007 |
| Project Title |
Project Description |
Agency Contact |
Telephone Number |
|---|---|---|---|
| Aptamer-Based Microarray for the Detection of Environmental Allergens | Environmental allergenic disease is a major cause of illness and disability in the United States, and there is broad consensus that the prevalence of type I-allergy is increasing worldwide. In spite of the substantial societal and health costs, the methods used to detect and quantify allergens in environmental health studies limit measurement to a few well characterized allergens that represent less than 10 percent of total allergen diversity. Recent advances in biotechnology have yielded potentially useful functional binding biomolecules (aptamers) that can enable low cost, high affinity allergen measurement. Aptamers are selected in vitro from combinatorial oligonucleotide libraries and therefore have several advantages over the traditionally used antibodies for detection of allergens. Among these advantages is higher stability, binding affinities greater than or equal to monoclonal antibodies, a dramatic decrease in production and assay cost, and the ability to target specific IgE binding epitopes of an allergenic protein. The overall goal of this research is to determine the feasibility of using aptamer-based methods for measuring environmental allergens. Two core development issues must be addressed to achieve this goal, and they form the basis for the first two specific aims. First, aptamers that are specific for the whole allergenic protein and aptamers that are specific for an IgE epitope binding peptide within the allergen will be produced via the SELEX method and their binding affinities characterized. Alternaria mold (Alt a 1) and dust mite (Der p 1) allergens will be targeted. Next, the aptamers will be tested in an inhibition type assay to determine cross reactivity, limits of detection, and the ability to mimic IgE epitope binding. Integrating the resulting aptamer-based allergen measurements to enhance quantitation in an ongoing and complementary environmental childhood asthma epidemiological study forms the basis for the third and final aim. Correlations between allergen specific IgE blood levels and environmental level of these allergens measured by antibody-based, aptamer-based, and specific IgE-based methods will be produced. Successful use of aptamers for measuring environmental allergens should lead to a more cost effective, flexible, and health relevant method and thereby provides the potential for a more fundamental understanding of the role of environmental allergens in respiratory health. Allergenic disease is a major cause of illness and disability in the United States. In spite of the substantial health and monetary costs, the methods used to study allergens in the environment are underdeveloped. The purpose of this research is to test the feasibility of a more flexible and low cost allergen measurement method (aptamers). The successful application of this aptamer technique should lead to a more cost effective and health relevant allergen detection method and enable a better understanding of disease caused by and exacerbated by environmental allergens. | David Balshaw | 919-541-2448 |
| Head-off Environmental Asthma in Louisiana (HEAL) | We are conducting a complex study in post-Katrina New Orleans named the Head-off Environmental Asthma in Louisiana Study (HEAL). The primary goal of HEAL is to implement and test an Asthma Counselor (AC) and environmental intervention program that addresses the multidimensional impact of hurricane Katrina on children with asthma in New Orleans. HEAL is a prospective, cross-sectional observational study. Approximately 200 families with children with moderately severe asthma (4-12 years of age) are enrolled in the HEAL program. All families receive an AC intervention focused on case management, adherence to medications and education on allergen avoidance. The responsibilities of the AC in this study are enhanced relative to previous initiatives such as the National Cooperative Inner City Asthma Study (NCICAS) AC intervention to also provide families with education aimed at reducing mold, allergens, and moisture in their homes, and materials to aid this effort (e.g., cleaning supplies, dust mite proof bed clothes, HEPA air filters and other). Since 90 percent of children with asthma in New Orleans are sensitive to dust allergens, established allergen control measures are incorporated into the AC intervention as well. The AC intervention is administered to families in the HEAL program over a 12-month period during which all children receive an extensive clinical evaluation (at baseline and 12 months), three environmental home evaluations (focused on moisture, mold and other allergens). During the clinical evaluation, allergen skin prick testing will be done to a standardized allergen panel as well as to 10-12 other molds currently found in high concentrations in New Orleans. Blood samples are collected and analyzed for total IgE and specific IgE to individual mold species using an interagency agreement between the National Toxicology Program and the National Institute for Occupational Safety and Health. This comprehensive skin testing of children to such a wide variety of relevant molds is a novel aspect of the study, and will significantly increase the current understanding of the validity of prick skin testing to these fungi since in vitro and in vivo methods of determining specific IgE will be compared. In addition, blood will also be archived for future genetic studies for susceptibility to mold and other environmental triggers of asthma. In addition to the clinical evaluation and monitoring the effectiveness of the AC and environmental intervention (periodic surveys), the study also entails three environmental home evaluations to allow some characterization of the relationships between mold, other allergens, post-Katrina environmental exposures and asthma morbidity. These evaluations are conducted at study baseline (shortly after the child's clinical evaluation), and then at 6 and 12 months afterward. The indoor home evaluation consists of: (1) an in depth visual inspection for mold, moisture, and other indoor allergen problems; (2) a verbal interview with the family; (3) the collection of dust samples from three different rooms (kitchen, living area, and child's bedroom); (4) the collection of indoor and outdoor air samples; and (5) the collection of the HEPA filters from units placed in the child's bedroom. The childrens bedroom dust samples will be analyzed by ELISA for mold, cat, mouse, roach, dust mite, endotoxin, and beta-D-glucans, and by PCR for up to 37 mold species (Steve Vesper at the EPA). The indoor air samples and about one-third of the outdoor air samples will be analyzed for total fungal spores, some genus identifications, pollen, and other air born particles. The HEPA filters will be analyzed for culturable mold and Actinomycetes. The remaining dust and air samples will be archived for future analyses as more funding becomes available. The HEAL project is a collaborative multi-institutional research project conducted by the Tulane University School of Public Health and Tropical Medicine and the New Orleans Department of Health. To support those efforts, Rho, Inc. provides for coordination of data and study activities. An active community advisory group (CAG) has been convened for the s | Patricia C. Chulada | 919-541-7736 |
| Toxicology Studies of Mold Exposures | The overall goal of this research project is to investigate the potential for molds found in damp or water damaged buildings to cause systemic toxicity. The specific aims of the proposed studies are to: (1) Assess organ system toxicity following inhalation exposure to molds, (2) evaluate the available biomarkers of exposure and effect (both general and specific for the organisms to be studied), and (3) evaluate the contribution of different organisms to overall health effects by studying individual isolates as well as mixtures. NTP will conduct subchronic studies in rodents using inhalation as the route of exposure. Pilot studies will examine feasibility with the duration of follow-up studies to be determined. Two mixtures and 4 isolates of individual organisms will be tested. There will be extensive characterization of the test materials (including an evaluation of relevant mycotoxins, glucans, allergens, particle size, protease activity, colony-forming units, spores, and endotoxin levels) both prior to and during the studies. Proposed test materials include: (1) Mixed culture of molds from a water damaged building from New Orleans, LA (2) Mixed culture of molds from a damp building with reported health effects (sick-building syndrome) (3) Stachybotrys chartarum isolate 1 (macrocyclic tricothecene chemotype) (4) Stachybotrys chartarum isolate 2 (atranone chemotype) (5) Aspergillus versicolor (6) Alternaria alternata Neurotoxicity will be evaluated using a functional observation battery, olfactory sensing, and cognitive tests. Particular attention will be paid to the cardiovascular, respiratory, gastrointestinal, and immune systems during histological evaluation as these organs have been reported to be potential targets following exposure to molds. Significance and expected outcome: These studies will provide important information regarding which fungal organisms may be causative agents for human health effects, target organs for fungal toxicity, the utility of biomarkers other than IgE as measures of exposure and effect, and dose-dependent effects with particular emphasis on respiratory, immune, and neurologic endpoints. | Dori Germolec | 919-541-3230 |
| Characterization of Floor Level Aerosol (PM) Exposure and Childhood Asthma | A research study is proposed to refine and evaluate a new device to improve the estimation of indoor exposure to inhalable particulate for both children in the first year of life and toddlers. Because they frequently play on the floor, these children may experience significantly higher levels of exposure than older children and adults to PM10 particles and airborne constituents, which are known asthmagens. A total of 200 children ages 6 to 35 months will be enrolled from neighborhood clinics. Parents will be administered a standardized asthma questionnaire (ISAAC) to determine presence and frequency of asthma symtpoms. Exposures will be characterized both qualitatively and quantitatively, to examine if the more precise estimation of PM10 exposure obtained by using a surrogate for personal monitoring. The study will employ a revised iteration of a prototype Pre-Toddler Inhalable Particulate Environmental Robotic (PIPER) Sampler that has been developed and undergone preliminary testing. Sampling will be carried out with both a fixed height stationary sampling station, where inlets of all instruments will be at 110 centimeters height, and the self-propelled computerized PIPER sampler, where inlets of all instruments can be varied between 20 to 110 centimeters above the floor to mirror the varied breathing heights of these children while engaged in play on the floor. Four parameters will be for each household: (1) mass concentration of PM10 particles measured by a real-time monitoring device, (2) real-time particle size and number distribution (0.3-10 urn), (3) air sampling on filters for detailed characterization of the PM10 constituents (pesticides, allergens, and endotoxins), and (4) concentration and composition of airborne fungi (viable and non-viable) collected on glass slides. Measurements will be collected in tandem for each of the 4 types of monitoring. The results of the laboratory analysis for endotoxins, molds and allergens for cockroaches (Bla g Yz), dust mites (Der f 1/p 1), dog (Can f 1), cat (Pel d 1) and mouse (Mus ml) will be evaluated for association with reporting of asthma symptoms. This study seeks to provide an alternative to personal monitoring for a variety of environmental exposures that may be experienced by children too young to be assessed by conventional methods, including those in their first year of life. In addition, it will open up an avenue for more precise estimation of early childhood exposures to asthmagens in the PM10 fraction of aerosols. | Kim Gray | 919-541-0293 |
| Columbia Center for Children's Environmental Health | The overall theme of the Columbia Center for Children's Environmental Health (CCCEH) is the identification and prevention of risks of neurodevelopmental impairment and childhood asthma from prenatal and postnatal exposure to urban pollutants. Since it was established in 1998, the Center has forged a successful partnership with West Harlem Environmental Action, Inc. (WE ACT), and nine other community organizations to identify and prevent environmental causes of childhood disease in Northern Manhattan and the South Bronx. The Center has enrolled and retained a unique cohort of mothers and children of color who belong to one of the most at-risk urban populations in this country with respect to environmental exposures, social adversity, and childhood health problems. Using molecular epidemiologic approaches, Center investigators have developed a rich body of knowledge about this vulnerable and disadvantaged urban population. They have documented substantial prenatal exposure to indoor and outdoor urban pollutants, including the combustion byproduct polycyclic aromatic hydrocarbons (PAH), environmental tobacco smoke (ETS), pesticides, and pest allergens. The research has demonstrated significant associations between prenatal exposures to those pollutants and adverse birth outcomes and/or neurodevelopmental, immunological, and respiratory health outcomes in children studied through age two. Building on its achievements of the past five years, the Center proposes several important new initiatives. These include follow-up of the mother and child cohort through ages five to seven, as the children enter school, with links to school performance data at age eight. Additional exposure, biomarker, and outcome assessments will allow testing of new etiologic hypotheses in the community based participatory research (CBPR) projects on asthma and growth and development. A new laboratory-based mechanistic research project will elucidate possible mechanisms of in utero sensitization by co-exposure to PAH/diesel exhaust particles and allergens, directly complementing the CBPR asthma project. A CBPR Intervention project on integrated pest management and health-related housing improvements will be conducted in partnership with the New York City Departments of Health and Mental Health and the New York City Housing Authority. A new Community Outreach, Translation, and Application Core (COTAC) will ensure that the Center's findings have local and national public health impact. COTAC initiatives will include: (1) education of medical students, medical residents, and pediatricians about children's environmental health; (2) a new community campaign to improve air and housing quality in New York City, co-led by WE ACT; (3) and risk assessment, cost, and risk prevention analyses on the Center's findings regarding the health effects of environmental exposures and the cost-effectiveness of IPM. In summary, it is important that the Center as an institution be continued as an established and valued resource to the community, scientific researchers, and policymakers. | Kim Gray | 919-541-0293 |
| Diesel, Allergens and Gene Interaction and Child Atopy | Allergic disorders affect over 40 million children, resulting in two million missed school days and costing society more than 10 billion/year. Atopy, defined as immediate hypersensitivity to specific allergens, is the strongest risk factor for child-onset asthma. The reported increasing incidence of atopic respiratory disorders is exaggerated in urban children living in westernized countries. There is intriguing scientific evidence demonstrating that diesel exhaust particles (DEP), a constituent of truck exhaust, promote expression of Th2 cytokines and production of IgE antibodies. The concern is that these exposures enhance clinical expression of IgE mediated respiratory disorders. Hence, children residing near interstate highways are at potentially high risk for exposures to truck emissions and resultant atopic respiratory disorders. In the Cincinnati metropolitan region, three interstate corridors intersect creating one of the busiest U.S. north/south and east/west commercial truck routes converging on a population of 1.9 million. The proposed investigation will follow two groups of children from birth through early childhood. The first group are children living within 400 meters of interstate highways. This group will be matched by birth date, race and income to a second group living beyond 1 km. There are two study purposes. The first is to measure DEP exposure levels and to determine if children with higher levels of exposure are at an increased risk for atopy and atopic respiratory disorders. The second is to determine if these effects are magnified in a genetically at risk subpopulation. The proposed study is a prospective cohort and nested case control design. The cohort of newborns will be evaluated prospectively for positive skin prick tests (SPT), allergic rhinitis and asthma. Residential exposures to DEP and aeroallergens also will be characterized longitudinally. The children who develop positive SPT will be matched by race and gender to controls having negative but the same number of SPT. The case control study will evaluate potential susceptiblity as measured by cytokine polymorphisms and to determine if exposure to DEP promotes the phenotypic expression of atopy and atopic respiratory disorders. This study design is optimum for determining if young children exposed to DEP have enhanced sensitization to aeroallergens and for dissecting gene-environment interactions. Results of this study may ultimately result in finding a preventable cause of atopic disorders in children. | Kim Gray | 919-541-0293 |
| HomeBase (Home-Based Asthma Support and Education for Adults) | The overall goal of this proposal is to understand better how to reduce asthma morbidity and health care utilization among low-income, ethnically diverse children ages 3-13. In particular, evidence about the effectiveness of in-home interventions, emphasizing control of environmental triggers relative to clinic-based interventions, is needed. One-half of the participants will receive clinic-based asthma education, self-management support (an asthma action plan and self-monitoring), resources for asthma control (allergy control bedding covers, a peak flow meter, and a medication spacer) and care coordination for one year from an asthma nurse (level 1 intervention). The other half will receive these services plus in-home environmental assessment, an individualized home action plan based on assessment data, education, and social support, encouragement of behavior changes, materials to reduce exposures (bedding covers, vacuums, door mats, cleaning kits, and a HEPA filter), and asthma self-management support for one year from a community health worker (level 2 intervention). A second goal is to learn how to adapt these interventions so they are culturally appropriate for ethnically diverse populations. A third goal is to reduce exposures to other household health risks such as lead, dust, asbestos, pesticides, other toxic household chemicals, and risks for injuries. A fourth goal is to develop better tools for assessing the indoor environment in community-based settings. A final goal is to integrate these activities into the work of the local asthma coalition. The investigators will conduct a randomized controlled trial with 360 subjects using parallel intervention groups and a wait-list control group to compare the effectiveness of the level 1 and 2 interventions with each other and the control group. Primary outcome measures will include asthma-related health status and quality of life, medical care utilization, and exposure to indoor asthma triggers (mites, roaches, mold, tobacco smoke, and pets). Secondary measures include knowledge of asthma, control of environmental triggers, and medical management; self-efficacy; and behaviors related to asthma control. They will assess the costs of the two levels of intervention from the perspective of a health services payer. The investigators hope this research will result in a replicable and sustainable model which can be adopted by health insurers and health care delivery organizations and integrated into a comprehensive, coordinated local asthma control system. The project's organization is based upon partnerships between parents of children with asthma, community-based organizations, public health agencies, and academia, and will follow principles of community-based collaborative research. It is sponsored by the King County Asthma Forum, a local asthma coalition with broad community participation from people with asthma, their families, and 34 agencies, including Public Health-Seattle & King County, the American Lung Association of Washington, the Asthma and Allergy Foundation of American, school districts, community health centers, hospitals, Seattle University, and the University of Washington. | Kim Gray | 919-541-0293 |
| Indoor and Outdoor NO2 and Asthma Severity in Children | Exposure to aeroallergens and air contaminants is hypothesized to be a major factor in the exacerbation of asthma. Results of our ongoing studies suggest that nitrogen dioxide (NO2) associated indoors with gas appliance use and outdoors with motor vehicle emissions, at levels well below the EPA Air Quality Standard, may be associated with respiratory symptoms in children at risk for developing asthma and with the exacerbation of asthma in asthmatic children. Our data are also suggestive of an interaction between indoor aeroallergens and NO2 concentrations in enhancing respiratory symptoms in infants and asthmatic children. The potential impact is great since 57 percent of homes in the United States use natural or LP gas, traffic volume is increasing and virtually all homes have significant dust allergen levels. We propose a prospective epidemiologic study of 1,533 children with active asthma (5 to 10 years of age), to test the hypothesis that carefully quantified NO2 concentrations associated with indoor sources and vehicle traffic on state and interstate roads are associated with asthma severity. In addition, we will determine if home levels of NO2, in the presence of common indoor dust allergens (Der p 1, Der f 1, Bla g 1, Pel d 1, Can f 1 and fungi), are associated with an increased risk of asthma severity in children sensitized to those allergens. The above hypotheses will be evaluated while adjusting for factors known or suspected to increase risk of more severe asthma, including household and school characteristics. The study population will be drawn from elementary schools in 16 Connecticut towns using a modified version of the ISAAC questionnaire to identify children with active asthma. Initial risk factors will be assessed in a home interview, and asthma severity (symptoms, frequency of ER visits, medication use, lung function) will be assessed prospectively for one year using telephone interviews administered quarterly. At the home visit, dust samples will be collected for allergen and fungi determinations and blood samples collected for antigen specific IgE determinations. Indoor and outdoor NO2 levels will be obtained quarterly for each home. Global Information Systems in combination with road vehicle density data will be used to assess the impact of traffic on asthma severity and outdoor NO2 concentrations at the home. Household gas appliances and traffic-related pollution may represent important environmental exposures for asthmatic children, for which effective interventions can be developed to reduce asthma morbidity. | Kim Gray | 919-541-0293 |
| Physical and Social Environmental Factors in Adult Asthma Outcomes | The proposed project will prospectively investigate physical and social environmental exposures as determinants of Health-Related Quality of Life (HRQOL) in adult asthma and rhinitis, focusing on the role of severity of disease as a principal mediator between the physical and social environment and HRQOL. The proposed study, a competitive renewal of an R01 near completion, builds upon our current research elucidating multifactorial models of physical and social environmental risks. The specific study aims are: (1) delineate the specific pathways linking physical and social environmental exposures to disease-specific and general HRQOL in adult asthma and rhinitis, including mediation by changing disease status overtime; (2) identify specific risk factors, such as personal socioeconomic status, that modify the impact of these environmental factors on disease severity or the effect of severity on HRQOL in adult asthma and rhinitis. To accomplish these goals, we will assemble a prospective cohort of 636 adults, merging our ongoing asthma-rhinitis cohort (the basis of the current R01) with a second cohort of adults with severe asthma established as part of a methodologically similar study. Subjects will undergo three waves of structured telephone interviews over the study period to ascertain environmental exposures, disease severity, and HRQOL. Two home visits will be conducted in a subset of subjects (n=380) to assess the home environment (including measurements of dust antigen, airborne particulate, and dampness), measure pulmonary function and exhaled fraction of nitric oxide, and collect biological samples to measure secondhand smoke exposure. We will also carry out geocoding for linkage to external data sets for U.S. Census information, traffic density, and levels of ambient air pollutants. We will test predictive models of physical and social environmental factors, including measures of indoor air quality, ambient pollution, and neighborhood and community status, estimating the longitudinal effect of these factors on HRQOL. We will assess the role of disease severity as a mediating factor in the causal pathway leading from environmental exposures to changes in HRQOL; we will also assess selected individual factors that may be effect modifiers of this relationship, especially personal socioeconomic status (SES). Public Health Importance: In order to understand the complex web of factors influencing airway disease outcomes from the perspective of persons with disease, there is a critical need for an analytic approach that can test the effect of multiple combined environmental risk factors on HRQOL, assess the mediating role of disease severity, and take into account individual effect modifiers. The long- term goal of our study is to identify modifiable factors and subgroups at high risk in order to improve HRQOL among adults with asthma. The proposed project builds upon our success in the current R01 by testing more specific pathways in the context of our accumulated experience to date. | Kim Gray | 919-541-0293 |
| Role of Diesel and Other Vehicular Exhaust in Exacerbation of Childhood Asthma | The burden of childhood asthma disproportionately affects children living in poverty and in urban centers, many of whom are minority ethnic groups. For those living in urban environments with high traffic densities, there is increasing concern about potential adverse respiratory health effects of exposure to diesel and other vehicular exhaust. Epidemiologic studies have shown associations between exposure to high traffic volumes, and especially to high truck traffic—the main source of diesel exhaust in urban settings—and increases in asthma symptoms, asthma hospitalizations, and decreased lung function. Yet, owing to the challenges of separating diesel from spark ignition exhaust, and vehicular exhaust in general from other sources of pollution, quantitative associations between exposure to diesel and other vehicular exhaust and adverse respiratory health outcomes have not been well-characterized. This study will characterize ambient exposures related to vehicular exhaust and other specific air pollutant sources, and evaluate the relationship of these exposures to the exacerbation of asthma among children living in Detroit and Dearborn, Michigan. We will collect ambient and indoor household air quality data which provides both high temporal and spatial resolution of pollution concentrations and utilize state-of-the-art statistical/geospatial models to apportion exposures among pollutant sources including diesel and other vehicular exhaust and to develop individual- specific exposure estimates. We will conduct a two-year longitudinal study involving 210 asthmatic children with 70 each living near high traffic/high truck volume roads, near high traffic/low truck volume roads, and distant from high traffic roads. Daily health measures to be assessed for two consecutive weeks in each of eight seasons will include respiratory symptoms, pulmonary function assessed by hand-held spirometers, medication use, and health services utilization. We hypothesize that: (1) exposures specific to diesel and other vehicular exhaust will be stronger predictors of adverse health status among children with asthma living in a high traffic density urban environment than other pollutant sources, and (2) the presence of cigarette smokers in the household, high levels of common allergens in household dust, or sensitization to such allergens, will yield stronger exposure-response relationships between diesel and other vehicular exhaust and adverse respiratory health outcomes. | Kim Gray | 919-541-0293 |
| Allosteric DNAzyme Sensors for Practical Detection of Mycotoxins | Mycotoxins are toxic compounds produced by fungi that contaminate crops during growth, transportation, or storage. Contamination of food and feed by mycotoxigenic fungi is an important agricultural and national security concern. For example, several thousand people are sickened annually by mycotoxicoses related to crops contaminated with fungi, and the safety of the food supply is integral to our national health and security. All of these issues demand the development of improved toxin sensor technologies. Current mycotoxin detection methods (e.g., those based on antibodies) have practical shortcomings both in the development of the sensors and in their applications. In this research project, we will develop innovative mycotoxin sensors based on allosteric DNAzymes, which are catalytic DNA molecules that are activated by binding of an analyte such as a mycotoxin. The long-term commercial objective of this project is to develop quantitative mycotoxin sensors for precise assays and also to develop semi-quantitative mycotoxin sensors for rapid field assays. This research will be performed with three specific aims: (1) apply in vitro selection to identify allosteric DNAzymes that have high selectivity and sensitivity to the mycotoxin deoxynivalenol (DON) and other mycotoxins such as fumonisin B1, zearalenone (ZON), and aflatoxin B1; (2) characterize and optimize the allosteric DNAzymes for toxin-sensing properties; and (3) engineer fluorimetric or colorimetric mycotoxin sensors by integrating fluorophore or gold nanoparticle detection systems with the DNAzymes identified in Aims 1-2. In later work, the allosteric DNAzyme sensors will be tested in the field to determine their absolute and relative efficacies as toxin detectors. This includes integration of the DNAzyme sensors with the standard storage and transport aeration system used in grain containment units, which will increase the assay sensitivities by concentrating analytical samples. Relevance to public health: Contamination of food and feed by mycotoxin-producing fungi is one of the most important agricultural and health-related problems in the United States and worldwide. Improved sensors for detecting mycotoxins and thereby revealing the presence of fungi will allow proper remedial actions to be taken. | Jerrold Heindel | 919-541-0781 |
| Fluorescent Multiplex Array for Indoor Allergens | Development of environmental tests to measure mold allergens using enzyme immunoassay (ELISA) and multiplex array technology (MARIA). This project is focusing on allergenic mold species, Alternaria and Aspergillus, as well as molds that arecommonly found in water damaged homes: Stachybotrys, Aspergillus versicolor, and Penicillium chrysogenum. Specific antibodies will be raised against each mold species and used for immunoassay purposes. The advantage of the MARIA technology is that multiple tests can be done at the same time on a dust or air sample. Both ELISA and MARIA are dependent of the production of well defined monoclonal or polyclonal antibodies to develop sensitive and specific tests. The aim of this project is to develop multiplex tests for a panel of molds that can be used to objectively assess mold exposure in homes, the workplace and public buildings. | Jerrold Heindel | 919-541-0781 |
| Epidemiology of Asthma: Risk and Prognosis in a Cohort from Birth to Adolescence | Asthma has shown dramatic increase worldwide. The disorder is diagnosed in 7-15 percent of U.S. children and is more prevalent in boys throughout childhood; however, during puberty a gender reversal occurs. We do not know if asthma persists in girls and remits in boys or if there is new onset asthma in girls. In addition, we do not understand factors driving these changes in asthma occurrence, but they seem to be related to gender- specific developments during puberty. We propose to test the following hypotheses: (1) gender reversal of asthma is due to new onset in girls and higher rates of clinical remission in boys; (2) risk factors include early onset of puberty, obesity, pollutants, and early life factors such as parental smoking and lack of breastfeeding; (3) identification of prognostic factors will allow for targeted interventions to prevent persistence and recurrence of asthma in adulthood. In 1989, we recruited a population birth cohort (1,456 children) on the Isle of Wight, an island one mile off the south coast of England with a population of 130,000. This cohort has been extensively phenotyped for asthma and other allergic diseases at 1, 2, 4 and 10 years of age. High follow up proportions (80-95 percent) have been achieved at each age. A wealth of information is available from prior examinations of the cohort. Participants are now adolescents. Therefore, this cohort is uniquely suited to address the above hypotheses. We propose to study these children at the age of 18 years and anticipate that 1,200 will participate. We will assess symptoms, lung function, airway inflammation, and atopic markers using questionnaire, physical examination, spirometry, bronchial provocation, exhaled nitric oxide, sputum induction, skin prick test, and total IgE. Using regression models with clinical markers as outcomes, we will determine the impact of pubertal factors, obesity-related factors (body mass index, serum leptin levels, genotypes for leptin and leptin receptor), and environmental risk factors (including, breastfeeding, tobacco smoke exposure, markers of pollution and agriculture exposure). Using all available information, we will determine a predictive model to identify children who are at high risk of persistent or recurrent asthma in adult life. These results will facilitate prevention of asthma persistence and recurrence. Our work brings together a multidisciplinary research team with a proven record of collaboration and expertise in respiratory medicine, allergy and immunology, epidemiology, genetics, and biostatistics. Note: As secondary objectives, this study correlates repeated measures (at age 6, 10, 18) of exposure (measured by questionaire on dampness in the home) and changes in sensitivity to allergens (obtained by skin test and total IgE) with development and/or progress of asthma. | James P. Kiley | 301-435-0233 |
| Maternal Vitamin D, Adiposity in Early Life, and Risk of Childhood Asthma | Asthma is the most common chronic disease of childhood in the developed world, and its prevalence in Western industrialized countries is increasing at an alarming rate. Maternal diet during pregnancy represents an important exposure with significant potential to modify immune function in offspring and hence the development of asthma and related atopic disorders in childhood. In addition, fetal growth may be a marker of prenatal processes that have large impact on asthma risk. Fetal growth is now known to be an indicator for risk of other chronic diseases, but the data regarding asthma are remarkably sparse. The goals of this application are to examine the potential impact of maternal dietary factors during pregnancy on the development of asthma and related disorders in early childhood, and to clarify the relationship between size at birth and incident asthma. A longitudinal prospective study is the most appropriate study design to evaluate these goals. This application takes advantage of the resources provided by Project Viva, an ongoing prospective cohort study of pregnant women and their infant offspring among members of Harvard Pilgrim Health Care, a large managed care organization in New England. Data already available from Project Viva include detailed dietary data on mother and infant, along with data on anthropometric, social, environmental, demographic, economic, psychological, and lifestyle variables. By following the Project Viva cohort until the ages of 3-4 years, the current application provides a relatively economical way to obtain updated exposure and outcome data, and to answer scientific questions of major public health importance. This work also brings together a multidisciplinary research team with a proven track record of collaboration and expertise in nutritional, respiratory, and pediatric epidemiology. Note: As a secondary objective, this study correlates exposure to mold/mildew, water in home basement (obtained by questionaire) and sensitization to Alternaria (obtained by blood sample tests for specific IgE) to development of asthma in children. | James P. Kiley | 301-435-0233 |
| Natural History of Asthma from Birth to Early Adult Life | Many of the factors associated with asthma risk in childhood are linked to lung function alterations in early adult life, which are related, in turn, to later asthma, COPD, and even death. The objective of this project is to assess prospectively the role of early life events and their interaction with genetic variation in determining risk for the development of symptoms and lung function alterations associated with adult asthma and COPD. The project has five specific aims: (1) to determine the relation of early lung function, wheezing LRIs, atopy, and bronchial hyperresponsiveness (BHR) to lung function and respiratory symptoms up to age 28; (2) to determine whether being overweight is associated with persistence of asthma-like symptoms, peak flow variability and airflow limitation to age 28; and whether genetic and developmental factors that control levels of and responses to leptin explain these associations; (3) to establish airway immune biomarker panels that distinguish specific asthma subphenotypes with their distinct pathogenetic mechanisms of development, and to establish the impact of variants in the IL-4 receptor alpha chain, MMP-9 and IL-8 genes on airway biomarkers within subphenotypes; (4) to investigate alterations in airway structure as measured by high- resolution computerized tomography in relation to early wheezing phenotypes, continued symptoms, lung function, BHR, allergen sensitization and biomarkers of airway inflammation; and (5) to assess the roles of (a) circulating levels of ligands of the epidermal growth factor receptor and related MMPs, and (b) variations in the genes encoding for these proteins, as determinants of the risk for asthma, lung function and BHR. We will use a combination of modern imaging approaches, molecular epidemiology, physiological lung function measurements, non-invasive assessment of airway inflammation, targeted genotyping and standard epidemiologic techniques to assess comprehensively the respiratory health of participants in the Tucson Children's Respiratory Study, a nonselected population followed from birth to their mid-20s. As the only respiratory study of adults which exhaustively recorded events occurring in the first 6 years of life, this approach will provide a unique opportunity to assess prospectively the role of early life events in determining risk for adult asthma and COPD. Elucidating these relations will foster the development of new strategies for the prevention and treatment of asthma and, potentially, of airflow limitation in adult life. This long-term study correlates measures of sensitization to specific allergens, including Alternaria (obtained by blood sample IgE and skin prick tests) to the development and progression of asthma and to lung function overtime. The study focuses on sensitization rather than measures of exposure. | James P. Kiley | 301-435-0233 |
| Stress, Environment, and Genetics in Urban Asthma | The overall goal is to examine the role of psychosocial stressors in a systems biology framework considering multiple biologic pathways by which stress can contribute to asthma causation. We will not only study the independent effect of stress on asthma/wheeze phenotypes in early childhood but also will consider stress as a modifier of physical environmental factors (allergens, cigarette smoking and diesel-related air pollutants) and genetic predisposition on asthma risk. We will determine the independent effect of maternal stress (both prenatal and postnatal) on early childhood asthma phenotypes. We further hypothesize that multi-life stressors prevalent in disadvantaged populations can cumulatively influence immune system development and airway inflammation in early life, thus making the populations more susceptible to other environmental factors and genetic risk factors explaining, in part, observed asthma disparities associated with SES and race/ethnicity. We will take a multi-level approach, measuring both individual-level stress (negative life events, perceived stress, pregnancy anxiety) and community-level stress (neighborhood disadvantage [e.g., percent of subjects living in poverty, percent unemployed], diminished social capital, and high crime/violence rates). We will also assess the influence of stress on the infant hormonal stress response and on T-helper cell differentiation as reflected in cytokine profiles and IgE expression (a topic or pro inflammatory phenotype). Additional physical environmental (indoor allergens, diesel-related air pollutants, tobacco smoke) and genetic factors will be assessed given their influence on the immune response and expression of early childhood asthma/wheeze. This interdisciplinary approach is unique because we are considering the context in which physical exposures and host susceptibility occurs, analyzing their multiplicative joint effects and considering multiple biologic pathways, as such it is consistent with the NIH roadmap objectives. As secondary objectives, sensitization (via blood sample and tests for specific IgE) to altenaria and the correlation of this sensitization to development of asthma in infants and young children. The study does not obtain measures of actual exposure to Alternaria allergen, either by questionnaire or home sample. | James P. Kiley | 301-435-0233 |
| The Role of Neutrophils in Hypersensitivity Pneumonitis | Hypersensitivity Pneumonitis (HP), or extrinsic allergic alveolitis, is an interstitial lung disease that develops following repeated exposure to inhaled environmental antigens. The disease is characterized by alveolitis and granuloma formation that in some patients progresses to fibrosis. The development of fibrosis in HP is associated with high morbidity rates; unfortunately the lack of information on disease pathogenesis has limited the development of therapies to treat the disease. Additionally, the disease is frequently misdiagnosed due to the variability of disease symptoms, differing diagnostic criteria, and a lack of understanding of the environmental antigens and host/genetic risk factors that lead to disease. The investigator's laboratory has been studying the role of IFN in the development of HP using the Saccharopolyspora rectivirgula (SR) animal model. IFN is a Th1 cytokine that is required for the development of granulomas in the lungs of mice following repeated exposure to SR. The production of IFN is important for the expression of T cell chemokines that recruit T cells into the lung following SR exposure; in the absence of IFN, T cell recruitment and subsequently granuloma formation are reduced. Therefore the cells that produce or regulate IFN production following SR exposure play a pivotal role in disease pathogenesis. The investigator's studies have revealed that neutrophils are a source of IFN during the early stages of HP and depletion of neutrophils prior to SR exposure results in decreased IFN expression. These results suggest that neutrophils play a critical role in the development of HP and understanding the mechanisms that regulate neutrophil recruitment and production of IFN may provide important new insights into disease pathogenesis. The goals of the study are: Specific Aim 1—to understand the role of neutrophils in driving IFN production in the lung following SR exposure. Specific Aim 2—to determine the role of pattern recognition receptors in neutrophil recruitment into the lung. | James P. Kiley | 301-435-0233 |
| Study on Biomarkers for Exposure to Stachybotrys Chartarum | The lack of proper biomarkers has greatly hampered investigations of the human health effects of the toxigenic fungus, Stachybotrys. Attempts to relate inhalation exposure to pulmonary, immune and neurological toxicities have had only circumstantial evidence supporting the apparent exposure. Epidemiological and pathophysiological studies would be greatly facilitated by the development of biomarkers that can be quantitatively related to the dose and timing of the exposure. We have recently found that purified satratoxin G, a macrocyclic trichothecene from Stachybotrys with two epoxides, forms stable adducts with human serum albumin. This offers the potential for quantitative biomarker 'dosimeters'in the form of protein adducts and related urinary metabolites in parallel to that used for the epoxide derivative of the mycotoxin, aflatoxin B1. Hypothesis: Inhalation exposure of humans to strains of Stachybotrys chartarum producing satratoxin G will result in the formation of covalent adducts of serum albumin and/or hemoglobin in sufficient quantities to be measured using mass spectrometry or radioimmune assay. This project proposes to: (1) complete the identification of the amino acyl satratoxin adducts of recombinant human serum albumin, determine the chemical structure of the adducts, and ascertain the relative reactivity of the amino acyl residues being modified; (2) confirm the presence of these adducts and/or metabolites in samples of biological materials including serum, red blood cells and urine from exposed rats and humans; (3) develop practical quantitative biomarker assays for satratoxin-albumin and hemoglobin adducts using exhaustive proteolysis and immunoaffinity chromatography with analysis by mass spectrometry and by radioimmune assay. Similar mass spectrometry assays will be developed for related urinary metabolites; and (4) develop parallel assays for macrocyclic trichothecenes in environmental dust samples. Relevance: Over the past decade there has been increasing public concern about the health effects of "toxic mold" or "black mold" (i.e. Stachybotrys) in home and work environments. The lack of objective tools to relate the amount of exposure to the observed health problems has hampered attempts to clearly demonstrate such mold-related health effects. This project proposes to develop quantitative assays for such investigations. | Srikanth Nadadur | 919-541-5327 |
| Study on Spore Dispersal and Germination in Stachybotrys Chartarum | This project is concerned with spore dispersal in the black mold Stachybotrys chartarum, a toxin-producing fungus of growing public health concern as a contaminant of water-damaged buildings. Human exposure to its spores has been associated with a variety of respiratory and neurological illnesses, including a cluster of idiopathic pulmonary hemorrhage (IPH) cases in infants in Ohio. The biological activity of Stachybotrys toxins is a subject of intensive research effort in other laboratories, but little attention has been paid to the mechanisms of spore dispersal that cast these compounds into the air. This project is motivated by the following question: How do the sticky spores of this mold move and contaminate the indoor environment? The first set of experiments will examine the effects of airflow, substrate vibration, and water movement on spore dispersal. The possibility that insects may act as vectors for dispersal of Stachybotrys spores will be the focus of a second aim. Thirdly, spore germination will be assessed using a multi-well plate method in relation to water availability, substrate composition, temperature, conidial age, and density of conidial deposits. These experiments will clarify both the mode of human exposure (an issue of major clinical significance), and the way that the mold spreads through buildings. | Srikanth Nadadur | 919-541-5327 |
| Chitinases and TGF-ß in Human Asthma (Subproject 3 of a solicited grant entitled "Mechanisms of Initiation and Persistence of Allergic Asthma") | This project seeks to determine the importance of chitins and chitinases in human asthma, with a focus on genetic variants of the chitinases. Chitin is a major structural component of fungi, crustaceans, helminths, and insects. Chitinases are chitin-degrading enzymes, and two occur in mammals, chitrotriosidase (CHIT1) and acidic mammalian chitinase. However their role in allergic airway inflammation and asthma is not well understood. A preliminary study demonstrated that one homozygous variant of CHIT1 protected study participants against sensitization to airborne fungal allergens. This project will examine the relationship of variation in the genes for chitinases to sensitization to four fungi (Alternaria, Aspergillus, Cladosporium and Penicillium), and to asthma. | Marshall Plaut | 301-496-1886 |
| (1) Initiation of Allergic Immunity by Parasites; (2) Innate and Adaptive Immune Cell Cross-Talk in Lung Allergy (Subproject 2 in the Solicited Grant Entitled "Mechanism of Initiation and Persistence of Allergic Asthma") | One investigator has two related studies. The first is an R01 grant that aims to determine whether chitin, a major structural component of fungi, as well as crustaceans, helminths, and insects, is a key molecule for inducing allergic inflammation, a central feature of allergy and asthma. This is a new area of research, and the role of fungal chitins has not previously been assessed. The studies will determine how chitin stimulates the innate and adaptive immune response and will identify an immune system receptor for chitin. The second study (subproject 2 of a U19) will focus on the potential role of Aspergillus-derived chitin in models of asthma and airway hyper-responsiveness, and will test whether chitin has one or both of two opposing functions: to either stimulate or limit allergic inflammation. | Marshall Plaut | 301-496-1886 |
| Planning a Multicenter Oral Itraconazole Trial in Chronic Rhinosinusitis Patients | This research project is intended to evaluate the hypothesis that, if the pathology of chronic rhinosinusitis is induced by an abnormal immune response to fungi, an anti-fungal agent will be an effective treatment of the disease. This clinical trial planning grant supports a one year effort to establish a multi-center research team from six medical centers; define patient recruitment strategies; and develop the study protocol, investigator's brochure, manual of operations, and tools for data management and research oversight. The clinical trial, which will require a separate grant application in the future, will investigate the efficacy of oral itraconazole, an anti-fungal agent, in treating patients with chronic rhinosinusitis with nasal polyps. The investigator has preliminary data suggesting that anti-fungal agents are beneficial, but this concept is controversial. This future trial is intended to resolve the controversy. | Marshall Plaut | 301-496-1886 |
| Relationship between Exposure to Airborne Fungi and Asthma in Inner City Children (a Component of the Inner City Asthma Study Grants) | The Inner City Asthma Study protocol to study the relationship between exposure to airborne fungi and asthma in inner city children includes an environmental intervention to reduce exposure to allergens and tobacco smoke. One component of the environmental research study focused on the role of exposure to fungi, combined with sensitization to these fungi as a determinant of the severity of asthma. This component of the study was completed in 2001 and preliminary analysis of the data indicates that the combination of exposure to fungi and sensitization is an independent risk factor for asthma severity. Fifty percent of children with asthma who enrolled in this study tested positive for Immunoglobulin E (IgE) antibody to at least one fungal extract. IgE is an antibody that participates in allergic reactions. This research also demonstrated that the levels for airborne fungi encountered indoors parallel the levels of fungi encountered outdoors. The levels of fungi encountered indoors were higher in homes with dampness problems, cockroach infestations, and cats. Fungal exposure levels were measured by collecting and culturing air samples and identifying and counting colonies of each fungal species. The study focused primarily on four species of fungi: Alternaria, Aspergillus, Cladosporium and Penicillium. Results for the children who were tested for IgE antibody responses against specific fungi indicated that 36 percent of the children tested positive for antibodies against Alternaria; 28 percent tested positive for antibodies against Aspergillus; 19 percent tested positive for antibodies against Cladosporium; and 13 percent tested positive for antibodies against Penicillium. | Marshall Plaut | 301-496-1886 |
| The Pathogenesis of Chronic Rhinosinusitis | This project will investigate a new hypothesis concerning the pathogenesis of chronic rhinosinusitis in humans; namely, that the pathology is induced by an abnormal immune response to fungi. Because chronic sinusitis is closely associated with asthma, an allergic-type immune response involving Immunoglobulin E (IgE) antibodies might be expected. However, prior studies by this investigator have demonstrated otherwise. Patients with chronic rhinosinusitis were shown to have exaggerated immune responses to airborne fungi, especially Alternaria, characterized by Immunoglobulin G (IgG) antibodies, particularly IgG4, and lack of IgE antibodies. Allergic reactions are characterized by the production of cytokines by T helper type 2 (Th2) cells. In chronic rhinosinusitis, not only Th2 cytokines, but also T helper type 1 (Th1) cytokines are produced. The grant will extend these findings to compare the immune responses in the blood and sinus tissues of patients with chronic rhinosinusitis to the responses in control participants. The grant will also support studies on the capacity of enzymes derived from Alternaria to activate eosinophils, which are white blood cells most characteristic of allergic inflammation. Eosinophilic inflammation is frequently present in the sinuses of patients with chronic rhinosinusitis. | Marshall Plaut | 301-496-1886 |
| A Novel Model of Fungal Asthma Using Aeroallergen Sensitization and Challenge | The purpose of this project is to develop a new mouse model to study allergy to the fungus Aspergillus fumigatus in which the fungus is delivered to the animals in the form of airborne spores. The investigators will test whether allergy can be induced in mice using this method and will compare their results to those obtained using the conventional model of allergic sensitization to Aspergillus in which the fungus is delivered in a liquid form. | Alkis Togias | 301-496-1886 |
| Environmental Proteinases in Human and Experimental Asthma (Subproject 2 of the Asthma and Allergic Diseases Cooperative Research Centers Grant Entitled "Innate Immunity in Allergic Airway Inflammation of Asthma") | The overall objective of this project is to identify early innate immune system signaling pathways that predispose an individual to chronic allergic airway disease. The innate immune system is the component of the human immune system responsible for the initial broad response to infection. The specific hypotheses being tested are that mold enzymes with proteolytic activity, also known as proteinases, that are present in house dust, are more common in the homes of children with asthma compared to children without asthma and are capable of promoting the development of sustained allergy in mice. Proteinases are not unique to mold; however preliminary findings from research supported by this grant indicated that in house dust samples, the only detectable proteinases are of fungal origin. | Alkis Togias | 301-496-1886 |
| Role of Fungal Microflora in Mucosal Tolerance/Immunity | This project addresses the hypothesis that disruption of the microbial community structure in the gastrointestinal tract by promoting the growth of fungi, such as Candida albicans, may facilitate the development of allergic disease to inhaled allergens. The project utilizes mouse models of asthma and sinusitis. A short course of antibiotics is first administered to the mice and they are then fed Candida albicans to promote colonization of the fungus in their gastrointestinal tract. This approach makes the animals susceptible to developing allergy against other molds. | Alkis Togias | 301-496-1886 |
| The Asthma Evaluation Study (ACE) (a Component of the Solicited Inner City Asthma Consortium Contract) | The Inner City Asthma Consortium Asthma Control Evaluation (ACE) study was designed to test the hypothesis that asthma control in low income, urban adolescents and young adults can be improved with the addition of exhaled nitric oxide as a marker for treatment guidance to conventional asthma management guidelines. Exhaled nitric oxide is a marker of airway inflammation; therefore, utilization of this marker to guide the management of asthma treatment could have decreased inflammation to a larger extent that conventional asthma management alone. The study was designed as a 12 month clinical trial and involved 546 participants. The study is complete and data analysis is ongoing. A secondary purpose of this study is to examine the role of allergy to molds in influencing the effectiveness of the asthma management plan. In this context, study participants underwent skin testing against a panel of common airborne allergens including the molds Alternaria tenuis, Cladosporium herbarum, a mixture of Aspergillus species, and Penicillium notatum. | Alkis Togias | 301-496-1886 |
| National Health and Nutrition Examination Survey 2005-2006 / Allergy and Asthma component | The National Health and Nutrition Examination Survey (NHANES) is a program of studies designed to assess the health and nutritional status of adults and children in the United States. In collaboration with NIAID/NIH and CDC/NCHS, we proposed a new allergy/asthma component to NHANES 2005-2006. The main goal of this new study component is to better understand the role that environmental exposures play in allergic sensitization and in the development of allergic diseases including asthma. The following procedures were performed as part of the component: (1) measurement of total and specific immunoglobulin E (IgE) to 19 indoor, outdoor, and food allergens in subjects older than 1 year of age; (2) vacuum dust collection from the bedroom of all subjects, (3) analysis of collected dust for 10 indoor allergens and endotoxin, and (4) administration of allergy and asthma related questionnaires. Two fungal allergens were included in the allergen measurements—Alternaria and Aspergillus. We anticipate that this extensive cross-sectional environmental dataset will generate novel hypothesis regarding the role of environmental exposures in allergy and asthma pathogenesis. In early 2008, this data will be made publicly available to all researchers. | Darryl Zeldin | 919-541-1169 |