INFLAMMATORY CELL SIGNALING BY CD36

CD36 的炎症细胞信号传导

• 批准号: 7337249
• 负责人: Roy L Silverstein
• 金额: $ 39.92万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337249
• 关键词: Address; Adipocytes; Apolipoprotein E; Apoptotic; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; CD36 gene; Cells; Chronic; Complementary DNA; Complex; Data; Development; Diabetes Mellitus; Disease; Elements; Foam Cells; Goals; Grant; Human; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin Receptor; Insulin Resistance; Knockout Mice; Lesion; Ligands; Link; Lipids; Lipoprotein (a); Lipoprotein (a-); Lipoproteins; Low-Density Lipoproteins; MAPK8 gene; Mediating; Mediator of activation protein; Metabolic Pathway; Metabolic syndrome; Mitogen-Activated Protein Kinases; Molecular; Mouse Strains; Mus; Obesity; Pathogenesis; Pathway interactions; Phospholipids; Play; Process; Publishing; RNA Interference; Reagent; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Technology; atherogenesis; cell motility; interest; macrophage; macrophage scavenger receptors; migration; monocyte; oxidized lipid; particle; programs; receptor; receptor function; response; scavenger receptor; uptake

THE Dpnwincn Interaction of atherogenic lipids with vascular cells plays a critical role in the formation and progression of atherosclerotic lesions. The goal of this project is to define the mechanisms by which CD36, a scavenger receptor for specific forms of oxidized phospholipid, mediates pro-atherogenic and pro-inflammatory responses. Recent studies suggest that scavenger receptor function in the vessel wall may be much more complex than simply serving as a conduit for uptake of atherogenic LDL particles and that intracellular signals triggered by the interaction of oxidized lipids with macrophage CD36 may induce responses that contribute to lesion development and plaque instability. New data obtained during the previous grant period shows that CD36-mediated signals led to activation of MAP kinases JNK-1 and -2. Given the central role of JNK in mediating pro-inflammatory responses and new studies linking pathogenesis of diabetes and insulin resistance to JNK activation, we propose that a CD36-dependent signaling pathway induced by the interaction of specific oxidized phospholipids with macrophages and adipocytes contributes to atherosclerosis and provides a mechanistic connection among atherosclerosis, inflammation, and insulin resistance. To explore this hypothesis, we will take advantage of unique reagents and expertise available through this new Program Project, including well characterized oxidized phospholipids that function as specific CD36 ligands, multiple cd36 null mouse strains, and technologies to transduce primary monocytes with cDNA and RNAi constructs. The 1st aim will define the role of specific oxidized lipid ligands in activating macrophage CD36, identify the molecular elements of the CD36 signaling pathway in macrophages, characterize the intracellular signaling pathways induced by CD36, and define the mechanisms by which CD36 cross talks with other vascular cell receptor signaling pathways, focusing on receptors of the innate immune system and insulin receptor. The 2nd aim will define mechanisms by which CD36 signals regulate specific macrophage functions; e.g. lipoprotein and apoptotic cell uptake, modulation of the inflammatory response, and cell migration.

的 Dpnwincn 致动脉粥样硬化脂质与血管细胞的相互作用在动脉粥样硬化的形成和发展中起着关键作用。 动脉粥样硬化病变本项目的目标是定义清除剂CD 36 特定形式氧化磷脂的受体，介导促动脉粥样硬化和促炎症 应答最近的研究表明，血管壁中的清道夫受体功能可能更多 复杂，而不是简单地作为摄取致动脉粥样硬化的LDL颗粒的管道， 由氧化脂质与巨噬细胞CD 36相互作用触发的信号可诱导应答， 导致病变发展和斑块不稳定。上一个赠款期获得的新数据 显示CD 36介导的信号导致MAP激酶JNK-1和JNK-2的活化。由于核心作用， JNK介导的促炎反应及糖尿病发病机制与胰岛素的关系 抗JNK激活，我们提出CD 36依赖性信号通路诱导的JNK激活， 特定氧化磷脂与巨噬细胞和脂肪细胞的相互作用有助于 并提供了动脉粥样硬化、炎症和胰岛素之间的机制联系 阻力为了探索这一假设，我们将利用现有的独特试剂和专业知识 通过这个新的计划项目，包括充分表征的氧化磷脂， 特异性CD 36配体、多种CD 36缺失小鼠品系和培养原代单核细胞的技术 用cDNA和RNAi构建体。第一个目标是确定特定的氧化脂质配体在激活 巨噬细胞CD 36，鉴定巨噬细胞中CD 36信号通路的分子元件， 表征由CD 36诱导的细胞内信号传导途径，并定义其机制， CD 36与其他血管细胞受体信号传导途径交叉对话，重点关注先天性 免疫系统和胰岛素受体。第二个目标将定义CD 36信号调节的机制。 特异性巨噬细胞功能;例如脂蛋白和凋亡细胞摄取，炎症调节， 反应和细胞迁移。