Diet-Environment Interactions in Inflammation

描述（由申请人提供）：我们最近证明，短期暴露于吸入颗粒物<2.5<（PM2.5）导致动脉粥样硬化的血管炎症。这种炎症反应可能是PM2.5介导其作用的关键综合机制。在这个提议中，我们假设PM2.5与高脂肪喂养相互作用，以增强先天免疫机制。我们建议通过一系列涉及广泛的跨学科小组的研究，使用模拟真实的世界环境暴露于PM2.5的颗粒暴露室，在易感和转基因/敲除模型中测试这一假设。在目的1中，将在暴露于PM2.5或过滤空气（FA）的C57 B1/6小鼠中评价单独的PM2.5和与高脂肪食物（HFC）组合对葡萄糖/胰岛素稳态、胰岛素信号传导、脂肪炎症的影响以及对这些影响最重要的PM2.5组分的分析。在目的2中，我们将研究PM2.5暴露与HFC饮食结合对炎症单核细胞活化，脂肪浸润和表型的作用，使用C57/B16和单核细胞特异性黄色荧光蛋白表达的转基因模型，在巨噬细胞集落刺激因子受体（CD 115，c-fms）启动子的控制下。我们将确定PM调节巨噬细胞功能和向脂肪和肺迁移的机制。在第三个具体目标中，我们将使用TLR 4-/- /MyD 88-/-/TLR 3-/-/NOD-/-小鼠，使用简化的气管内递送途径筛选PM2.5对TLR 4的特异性。随后在TLR 4-/-/MyD 88-/-小鼠中进行体内暴露，以评估对胰岛素抵抗的影响。为了鉴定巨噬细胞的特异性贡献，我们将使用可用的TRAF 6 Flox/Flox小鼠产生TLR 4、TRAF 6的下游介质的组织特异性条件性敲除，并测试其对胰岛素抵抗/炎症的作用。使用最先进的暴露系统结合炎症机制的最新进展，该提案提供了一个前所未有的机会来阐明PM2.5对胰岛素抵抗和炎症发病机制的影响的生理相关机制。从这些研究中收集到的见解具有重大的公共卫生影响，并可能最终导致适当设计的人类研究，最终导致政策变化，以避免环境暴露于PM2.5。

DESCRIPTION (provided by applicant): We have recently demonstrated that short-term exposure to inhaled particulate matter <2.5< (PM2.5) results in vascular inflammation in atherosclerosis. This inflammatory response may represent a key integrative mechanism through which PM2.5 mediates its effects. In this proposal, we hypothesize that PM2.5 interacts with high fat feeding to potentiate innate immune mechanisms. We propose to test this hypothesis in predisposed and transgenic/knock out models through a series of studies involving a broad inter-disciplinary group, using a particle exposure chamber that simulates real world ambient exposure to PM2.5. In Aim 1, the effect of PM2.5 alone and in combination with high fat chow (HFC) on glucose/insulin homeostasis, insulin signaling, adipose inflammation and an analysis of PM2.5 components most responsible for these effects will be evaluated in C57Bl/6 mice exposed to PM2.5 or filtered air (FA). In Aim 2, we will investigate the role of PM2.5 exposure in conjunction with HFC diet on inflammatory monocyte activation, adipose infiltration and phenotype using C57/Bl6 and a transgenic model of monocyte specific yellow fluorescent protein expression, under the control of a macrophage colony stimulating factor receptor (CD115, c-fms) promoter. We will identify mechanisms by which PM modulates macrophage function and migration to adipose and lung. In the third specific aim, we will screen specificity of PM2.5 for TLR4 using TLR4-/- /MyD88-/-/TLR3-/-/NOD-/- mice using an abbreviated intra-tracheal route of delivery. This will be followed by in-vivo exposures in TLR4-/-/MyD88-/- mice to assess effects on insulin resistance. To identify a specific contribution of macrophages we will generate a tissue specific conditional knock-out of a downstream mediator of TLR4, TRAF6 using an available TRAF6Flox/Flox mouse and test its effects on insulin resistance/inflammation. Using state of the art exposure systems in conjunction with the latest advances in inflammatory mechanisms, this proposal offers an unprecedented opportunity to elucidate physiologically relevant mechanisms responsible for the effects of PM2.5 on the pathogenesis of insulin resistance and inflammation. The insights gleaned from these studies have significant public health ramifications and may eventually lead to appropriately designed human studies eventually culminating in policy changes to avert environmental exposure to PM2.5.