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

描述(由申请人提供)：南加州儿童环境健康中心(SC-CEHC)正在研究无处不在的环境近道路空气污染(NRAP)对儿童肥胖和相关的2型糖尿病风险的作用。一个多学科团队正在利用南加州儿童健康研究的资源，利用基于人群的临床和实验研究的综合计划，利用队列中超重/肥胖的年轻人的尖端暴露评估、成像和代谢表型，检查终身累积NRAP暴露与脂肪组织炎症和相关代谢结果(包括脂肪分布、葡萄糖稳态、脂类分布和全身炎症)之间的关系。脂肪组织炎症的免疫调节作用日益被认为是肥胖人群糖尿病和代谢性疾病发展的核心；因此，中心面临的一个关键问题是NRAP对脂肪组织免疫细胞图谱的影响。然而，这是一个快速发展的领域，我们的研究小组和其他人最近的研究表明，免疫系统的先天和适应性手臂的额外成员，特别是T效应(T Effer)和T调节(Treg)细胞，调节脂肪组织炎症、胰岛素抵抗和糖尿病的发病机制。此外，最近的一份报告发现，暴露在颗粒物空气污染中的儿童外周血中TJeff细胞的表达减少。除了我们在该中心的最初目标是检查脂肪组织中的巨噬细胞极性之外，我们现在建议在60名超重/肥胖队列参与者中测量血液和深(筋膜下)皮下脂肪组织(DSAT)中的T细胞和Treg细胞数量。这些受试者将是一个由200名参与者组成的小组，他们是根据终生NRAP暴露从队列中根据信息选择出来的，正在中心接受详细的代谢评估。我们假设，终生接触NRAP会增加血液和脂肪组织中促炎的TJeff细胞数量，减少抗炎的Treg细胞，这些细胞将与DSAT的炎症和胰岛素抵抗有关。这些结果将被用来改进一个创新的潜在变量分层统计模型，该模型整合了跨项目的信息，以检查免疫表型对NRAP对代谢风险的影响，使用来自近5000名儿童的整个队列的信息。SC-CEHC提供了一个机会来解决我们在了解空气污染与2型糖尿病风险因素之间潜在的免疫机制方面的关键空白，并为未来的表达途径评估创造一个资源，如果能够及时提供支持，以表征在紧迫的时间框架内正在进行招募的受试者的新鲜组织。

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.