Diet-Environment Interactions in Inflammation

炎症中的饮食与环境相互作用

• 批准号: 8282851
• 负责人: Sanjay Rajagopalan
• 金额: $ 37.35万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282851
• 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

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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：我们最近证明，对吸入颗粒物的短期暴露<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介导其作用的关键整合机制。在此提案中，我们假设PM2.5与高脂进食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群体的研究，使用粒子暴露室模拟现实世界环境暴露于PM2.5的一系列研究来检验这一假设。在AIM 1中，单独使用PM2.5并与高脂肪Chow（HFC）结合使用葡萄糖/胰岛素稳态，胰岛素信号传导，脂肪炎症以及对这些效果最负责的PM2.5组件的分析，将在C57BL/6小鼠中评估为PM2.5或过滤空气（FA）。在AIM 2中，我们将研究PM2.5暴露与HFC饮食结合使用的作用在巨型刺激因子受体CD115，C-FMS的控制下，使用C57/BL6使用C57/BL6使用C57/BL6以及单核细胞特异性黄色荧光蛋白表达的转基因模型的作用。我们将确定PM调节巨噬细胞功能并迁移到脂肪和肺部的机制。在第三个特定目的中，我们将使用TLR4 - / - /myd88 - / - /tlr3 - / - /nod-/ - 小鼠使用缩写的传递途径，使用TLR4 - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - /tlr4。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下游介体的组织特异性敲除，并测试其对胰岛素耐药性/炎症的影响。该提案结合使用最新的炎症机制进展，提供了前所未有的机会，以阐明负责PM2.5对PM2.5对胰岛素抵抗和炎症发病机理的影响的前所未有的机会。这些研究收集的见解具有重大的公共卫生后果，最终可能导致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。 公共卫生相关性：拟议的工作通过环境PM暴露系统整合了最新的环境暴露状态，并在炎症，炎症细胞和血管功能障碍方面取得了最新进展。由于颗粒暴露，炎症，胰岛素抵抗和脂肪生物学的领域本身就很复杂，因此该提案中的工作将由经验丰富的研究人员和顾问来完成，这些研究人员和顾问以其贡献而闻名。完成后，这项工作将提供将非常重要的公共健康重要性的数据，希望该提案的结果将推动最终的政策变化，以遏制该国和全球范围内的颗粒物排放。