Genetics and ambient air pollutants are contributors to childhood respiratory diseases;however, gaps in the scientific knowledge base concerning the roles of specific sources, components and characteristics of air pollution and the role of inter-individual variation in susceptibility to air pollution's adverse effects impede effective intervention. The overall objective of the proposed program of research is to address these key gaps by investigating the contribution of genetics and exposure to air pollutants during childhood to the occurrence of asthma and deficits in lung function growth. Accordingly, the overall theme of the program project remains "Genetics, air pollution and children's respiratory health." The program of research proposed in this application builds on the rich health, exposure and genetic data resources of the Children's Health Study (CHS), an ongoing cohort study investigating both genetic and environmental factors related to children's respiratory disease in over 11,000 southern California children. The research hypotheses are based on mounting evidence that oxidant gases, traffic-related exposures and specific combustion-exhaust particle-bound constituents activate oxidative/nitrosative stress and inflammatory pathways and contribute to respiratory morbidity. Our research questions target the following health issues: (1) Are chronic respiratory health effects associated with exposure to near source combustion particles from vehicular exhaust? (2) Do PM mass in specific size fractions (PM[0.25], PM[0.25-2.5], and PM[2.5.-10]) or specific size-fractionated constituents (e.g., water-soluble or total organic carbon, elemental carbon, or selected transition metals) affect health? (3) Do genetic variants involved in innate or adaptive immune responses or nitrosative/oxidative stress pathways contribute to respiratory disease, deficits in lung development, or differences in susceptibility to the adverse effects of near source combustion products or regional gaseous or particulate pollutants? These questions will be investigated in three inter-related projects with support from three cores (Exposure Assessment, Integrative Health Sciences, and Biostatistics and Data Management). The projects will evaluate the relationship between respiratory health (asthma, lung function growth, exhaled NO) and combustion particulate and gaseous pollutants;examine genetic variation in key pathways that modulate response to air pollution and disease occurrence;and develop new biostatistical methods for GxE studies and integrated analysis across multiple outcomes and exposures. Building upon our large and wellcharacterized children's cohorts, rich exposure data, and substantial genetic resources, our collaborative multidisciplinary team will apply an integrative approach to efficiently address key gaps in the knowledge base needed for timely and effective disease prevention and treatment.