Research Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory lung diseases that affect an estimated 35 million Americans. Endotoxin is derived from gram negative bacteria, and has been associated with both asthma and COPD. Endotoxin is almost universally present, and has been found at high levels in tobacco smoke, homes burning biomass fuel, in the context of various occupations especially cotton textile work, and more recently as part of indoor air pollution in schools. We do not fully understand how endotoxin can lead to development or worsening of asthma and COPD. Recent technologic advances have allowed one to simultaneously identify changes in expression of over 14K genes using microarrays. Studies comparing gene expression changes from invasive samples taken from the bronchi (lower airways) and non- invasive samples from the nose (upper airways) have shown many similarities. Studying how endotoxin affects the airways using gene expression changes is an important opportunity to further understand the relationship between endotoxin and lung disease. In this career development proposal, the applicant hypothesizes that endotoxin leads to distinct gene expression changes in the airways. These gene expression changes reflect underlying dysregulated pathways in lung disease that can serve as a biomarker for susceptibility to disease exacerbation, disease development, or clinically important subtypes of lung disease. She proposes to examine the impact of current high endotoxin exposure on airway gene expression in a cohort of inner-city elementary school children with and without asthma. She then proposes to evaluate whether prior endotoxin exposure leads to persistent changes in airway gene expression, even after years of exposure cessation, in a cohort of textile workers. Finally, she proposes to evaluate whether these gene expression changes are markers for important disease-specific subphenotypes, specifically "exacerbation prone" asthmatics in the school study and "emphysema type" COPD in the textile study. These studies take advantage of the sound study infrastructure present in two already existing and unique cohort studies, and will provide novel insights into the ways nasal gene expression can be used to understand the effects of chronic endotoxin exposure in a field setting. The successful completion of this research will help us understand the genes and biological pathways that are affected by chronic high endotoxin exposure, identify people who are susceptible to endotoxin-related asthma exacerbations, determine whether the type of COPD (emphysema vs. airways disease) can be identified using a simple gene expression based test, and may lead the way to the development of new therapies for endotoxin related lung disease. Additionally, it further characterizes the importance of school endotoxin exposure in asthma morbidity, and may shift the focus from home to school environmental controls for children with asthma. Candidate The applicant's long-term career goal is to become an independent clinical/translational NIH funded investigator focused on patient-oriented research in environmental lung disease. In order to achieve this goal, her short-term career objectives are to obtain further didactic training in environmental epidemiology, advanced biostatistics, genomics, and data mining, as well as practical skills in building a cohort, exposure assessment, obtaining biospecimens, nucleic extraction, selection of appropriate microarray technology, and analytic work in interpreting the output. This will be accomplished with formal classes that complement the candidate's prior coursework in completing a Master of Public Health, fieldwork and collaborative work to learn how to measure environmental endotoxin exposure and to recruit, consent, and maintain a cohort, benchwork using molecular methods, attendance at institutional and national conferences, and guidance from established mentors and a multidisciplinary advisory board with the relevant expertise. This will result in a unique combination of practical skills and scientific knowledge that will help her achieve independence from her mentorship team and prepare her to achieve her long-term career goal. Environment The applicant will perform her research training and career development activities at world-renowned major academic institutions. The division in which she will work is one that has a collaborative environment with both a rich research environment and an intense clinical focus, and has an outstanding history of mentorship, leadership in pulmonary and critical care medicine, and clinical excellence. Her institution is very invested in the applicant's successful career development, and will make available all the facilities, resources, and equipment needed for her career development and proposed research. Her mentors are nationally and internationally renowned experts in pediatric asthma and environmental and molecular epidemiology, and will provide full access to the resources accompanying two unique cohorts of endotoxin exposed children and adults.

Public Health Relevance

Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory lung diseases that affect an estimated 35 million Americans. Endotoxin is a near universal exposure that is derived from gram negative bacteria, and has been associated with both asthma and COPD. The goal of this study is to identify airway gene expression changes due to chronic high endotoxin exposure in inner city schools and textile mills, and to determine whether these gene expression changes can identify important mechanisms of disease and serve as a clinically useful biomarker for important asthma and COPD subtypes.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZES1-LWJ-D (K9))
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Shreffler, Carol K
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Massachusetts General Hospital
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Lai, Peggy S; Hang, Jing Qing; Zhang, Feng Ying et al. (2014) Gender differences in the effect of occupational endotoxin exposure on impaired lung function and death: the Shanghai Textile Worker Study. Occup Environ Med 71:118-25
Baxi, Sachin N; Muilenberg, Michael L; Rogers, Christine A et al. (2013) Exposures to molds in school classrooms of children with asthma. Pediatr Allergy Immunol 24:697-703