Prenatal diesel exposure and adult onset asthma

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Asthma has long been considered a complex genetic disease that is subject to environmental triggers experienced over a lifetime. Yet more recent evidence suggests that the onset of asthma may be modulated by intra-uterine environmental exposures. Exposure to diesel exhaust particles (DEP) has been associated with decreased lung formation. In addition, higher DEP exposure has been associated with a greater risk of becoming sensitized to pollen, and with up regulation of Th2 cytokines thought to underly atopy or allergic asthma. But despite growing evidence implicating prenatal allergen exposure to the subsequent onset of asthma-related phenotypes, the modulatory role of prenatal exposure to DEP to the later onset of asthma has not been elucidated. Furthermore, the mechanisms, including the impact of prenatal DEP exposure on lung development and differential gene expression, have not been studied. We hypothesize that prenatal diesel exposure can increase the risk for adult-onset asthma. Our strategy will be to study the effects of prenatal DEP exposure to asthma by employing reliable mouse models for antigen-specific sensitization and using them to study phenotypes associated with adult asthma, including augmented IgE production, commitment to the Th2 lineage, airway hyperreactivity, and airway remodeling. We predict that prenatal DEP exposure will lead to increased IgE class switching and Th2 differentiation, thereby promoting the risk for adult-onset asthma. We also predict that lung developmental changes and/or differential gene expression detected following in utero exposure to DEP will be associated with adult asthma. We anticipate that a study of the importance of immunologic and genetic responses to intra-uterine environmental stimuli, and their impacts on later disease, could lead to a better understanding of the role of environmental pollutants to asthma pathogenesis, and ultimately better strategies for prevention. Specifically, we propose to: Aim 1: Determine whether prenatal DEP exposure augments IgE production and commitment to Th2 lineage in the offspring. Aim 2: Determine whether prenatal DEP exposure is associated with altered epithelial cell differentiation in the developing lung. Aim 3: Determine whether prenatal DEP exposure is associated with increased airway hyper reactivity or airway remodeling in adult mice. Aim 4: Determine a) the differential gene expression following in utero diesel exposure, and b) whether differential gene expression following prenatal diesel exposure is associated with adult asthma.