Air pollution, immune modulation of adipose tissue and type-2 diabetes risk factors

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DESCRIPTION (provided by applicant): The Southern California Children's Environmental Health Center (SC-CEHC) is studying the role of ubiquitous ambient near-roadway air pollution (NRAP) on childhood obesity and associated risk for type 2 diabetes. A multidisciplinary team in an integrated program of population-based, clinical and experimental research is capitalizing on resources of the Southern California Children's Health Study to examine the association of lifetime cumulative NRAP exposure to adipose tissue inflammation and related metabolic outcomes including fat distribution, glucose homeostasis, lipid profile, and systemic inflammation using cutting edge exposure assessment, imaging and metabolic phenotyping in overweight/obese young adults from the cohort. The role of immune modulation of adipose tissue inflammation is increasingly recognized as central to the development of diabetes and metabolic disease in obese people; therefore, a key question for the Center is the impact of NRAP on the immune cell profile of adipose tissue. However, this is a rapidly evolving field, and recent studies from our research group and others indicate that additional members of the innate and adaptive arms of the immune system, in particular T effector (Teff) and T regulatory (Treg) cells, modulate the pathogenesis of adipose tissue inflammation, insulin resistance and diabetes. In addition, one recent report found decreased expression of Teff cells in peripheral blood of children exposed to particulate air pollution. In addition to our original aims in the Center to examine macrophage polarity in adipose tissue, we now propose to measure Teff and Treg cell number in blood and in deep (subfascial) subcutaneous adipose tissue (dSAT) in 60 overweight/obese cohort participants. These subjects will be a sub-group of 200 participants who have been informatively selected from the cohort based on lifetime NRAP exposure and who are undergoing detailed metabolic evaluation in the Center. We hypothesize that lifetime NRAP exposure will increase pro-inflammatory Teff cell count and decrease anti-inflammatory Treg cells in blood and adipose tissue, and that these cells will be associated with inflammation and insulin resistance in dSAT. The results will be used to refine an innovative latent variable hierarchical statistical model integrating information across projects to examine the influence of immune phenotype on the effects of NRAP on metabolic risk, using information from the entire cohort of almost 5000 children. The SC-CEHC provides an opportunity to address key gaps in our understanding of the immune mechanisms underlying associations of air pollution with risk factors for type 2 diabetes and to create a resource for future evaluation of expression pathways, if support can be provided in time to characterize fresh tissue in subjects undergoing recruitment on a tight timeframe.