Diet-Environment Interactions in Inflammation

炎症中饮食与环境的相互作用

基本信息

批准号：
8477189
负责人：
Sanjay Rajagopalan
金额：
$ 37.66万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-28 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477189
关键词：
Acetylgalactosamine Adhesions Adipose tissue Affect Air Pollution Airborne Particulate Matter Alveolar Macrophages Animals Area Atherosclerosis Biological Biology Biometry Blood Blood Vessels Bone Marrow Breathing CSF1R gene Cells Chemosensitization Childhood Complex Country Data Development Diabetes Mellitus Diet Disease Dose Environment Environmental Exposure Equilibrium Exposure to Fatty acid glycerol esters Flow Cytometry Functional disorder Galactose Gene Expression Generations Glean Glucose Grant Hematopoietic Homeostasis Human Immune In Vitro Inbred NOD Mice Infiltration Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Insulin Signaling Pathway Knock-out Lead Lectin Liver Lung Macrophage Activation Macrophage Colony-Stimulating Factor Receptor Measures Mediating Mediator of activation protein Metabolic Michigan Microscopy Modeling Mus Natural Immunity Non-Insulin-Dependent Diabetes Mellitus Obesity Particulate Particulate Matter Pathogenesis Pathway interactions Pattern recognition receptor Phenotype Policies Principal Component Analysis Principal Investigator Proteins Public Health Research Personnel Role Route Science Seasons Series Signal Pathway Signal Transduction Simulate Skeletal Muscle Source Specificity Structure of parenchyma of lung System TLR2 gene TLR3 gene TLR4 gene TRAF6 gene Testing Time Tissues Transgenic Model Transgenic Organisms Universities Visceral Work adipokines air filter base c-fms Proto-Oncogenes design experience feeding global health in vivo insight insulin sensitivity insulin signaling macrophage male migration monocyte particle particle exposure promoter protein expression public health relevance research study response toll-like receptor 4 vascular inflammation

项目摘要

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.

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）会导致动脉粥样硬化的血管炎症。这种炎症反应可能代表了 PM2.5 介导其影响的关键综合机制。在此提议中，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，使用模拟真实世界环境中 PM2.5 暴露的颗粒暴露室，在预设模型和转基因/敲除模型中测试这一假设。在目标 1 中，将在 C57Bl 中评估单独使用 PM2.5 以及与高脂食物 (HFC) 结合使用对葡萄糖/胰岛素稳态、胰岛素信号传导、脂肪炎症的影响，以及对造成这些影响最重要的 PM2.5 成分的分析。 /6 只小鼠暴露于 PM2.5 或过滤空气 (FA)。在目标 2 中，我们将使用 C57/Bl6 和单核细胞特异性黄色荧光蛋白表达的转基因模型（在巨噬细胞的控制下）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集落刺激因子受体（CD115、c-fms）启动子。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 TLR4-/- /MyD88-/-/TLR3-/-/NOD-/- 小鼠，采用简化的气管内递送途径，筛选 PM2.5 对 TLR4 的特异性。随后将在 TLR4-/-/MyD88-/- 小鼠中进行体内暴露，以评估对胰岛素抵抗的影响。为了确定巨噬细胞的特定贡献，我们将使用可用的 TRAF6Flox/Flox 小鼠对 TLR4、TRAF6 下游介质进行组织特异性条件敲除，并测试其对胰岛素抵抗/炎症的影响。该提案利用最先进的暴露系统与炎症机制的最新进展相结合，为阐明 PM2.5 对胰岛素抵抗和炎症发病机制影响的生理相关机制提供了前所未有的机会。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体研究，最终导致政策变化，以避免环境暴露于 PM2.5。