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.
The work proposed integrates state of the art environmental exposure using an ambient PM exposure system with recent advances in inflammation, inflammatory cells and vascular dysfunction. Since the fields of particle exposure, inflammation, insulin resistance and adipose biology are complex in of themselves, work in this proposal will be accomplished by experienced investigators and consultants who are internationally known for their contributions. On completion this work will provide data that will be of considerable public health importance and it is hoped that the results from this proposal will drive eventual policy changes to curb particulate emissions in this country and world-wide.
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