INTEGRATIVE GENETIC APPROACHES TO GENE-AIR POLLUTION INTERACTIONS IN ASTHMA

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PROJECT SUMMARY Numerous epidemiological studies have shown the adverse effects of traffic-related air pollution exposure on asthma and related phenotypes. Recent emerging evidence suggests that altered hematopoietic stem/progenitor cell (HSPC) homeostasis is one potentially important biological mechanism mediating the adverse effects of traffic-related air pollution on asthma. For example, hematopoietic progenitor cells (HPCs) are mobilized following inflammatory events in the lung, suggesting that these bone marrow (BM)-derived cells directly contribute to lung repair in response to injury. Accumulation of eosinophils and basophils in the lung is also a characteristic of allergic inflammation and is directly related to changes in the levels of eosinophil and basophil progenitors in the peripheral circulation. It is also likely that genetic factors modulate these effects, although direct evidence for this notion is currently lacking. Our provocative preliminary findings support this concept and demonstrate that the frequency of circulating HPCs in response to diesel exhaust particles (DEP), a model traffic-related pollutant, varies ~8-fold among 9 inbred mouse strains and is inversely correlated with airway hyperreactivity (AHR). Based on these observations and the integrative approaches currently being used to investigate gene-environment (GxE) interactions in asthma, we have assembled a highly experienced trandisciplinary research team to comprehensively investigate the interrelationships between genetic factors, traffic-related air pollution, HSPC homeostasis, and asthma. As part of this ViCTER proposal, this group will lead three collaborative research projects aimed at 1) determining the effects of DEP on the repertoire of HSPC subtypes in BM and peripheral blood and their relationships to AHR in a panel of inbred mouse strains; 2) applying innovative statistical genetics methods to identify GxE association for HSPCs and asthma-related phenotypes in both mice and humans; and 3) determining the effects of genetic factors and traffic-related air pollution exposure during prenatal development on HSPC subtypes in human umbilical cord blood samples. These coordinated activities involve well-characterized human cohorts, the generation of new immunophenotypic data in the same mice as in ongoing studies, de novo collection of human HSPC data, and the application of novel statistical methodology that overcome limitations of current analytical approaches. The results of these efforts could have a significant impact on our understanding of GxE effects in asthma and reveal underlying biological mechanisms involving HSPC biology that may have important biological, epidemiological, and translational implications for respiratory diseases. Taken together, the proposed studies expand and complement the scope of current projects in an efficient manner and will generate a synergistic research program among a team of investigators with the requisite expertise to successfully achieve the goals of the proposed studies.