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.

这 dpnwincn 动脉粥样硬化脂质与血管细胞的相互作用在形成和进展中起着至关重要的作用 动脉粥样硬化病变。该项目的目的是定义CD36（清道夫）的机制 特定形式的氧化磷脂的受体，可介导促动脉粥样硬化和促炎性 回答。最近的研究表明，在血管壁中的清道夫受体功能可能更多 复杂不仅是用作摄取动脉粥样硬化LDL颗粒的导管，该细胞内 由氧化脂质与巨噬细胞CD36的相互作用触发的信号可能引起反应 有助于病变发育和斑块不稳定。在上一个赠款期间获得的新数据 表明CD36介导的信号导致MAP激酶JNK-1和-2的激活。鉴于中心作用 JNK介导促炎反应和新研究，与糖尿病的发病机理联系起来 对JNK激活的抗性，我们提出了由CD36依赖性信号通路 特异性氧化磷脂与巨噬细胞和脂肪细胞的相互作用有助于 动脉粥样硬化，并在动脉粥样硬化，炎症和胰岛素之间提供机械联系 反抗。为了探讨这一假设，我们将利用独特的试剂和可用的专业知识 通过这个新的程序项目，包括具有良好特征的氧化磷脂 特定的CD36配体，多个CD36无效小鼠菌株和转导原代单核细胞的技术 与cDNA和RNAi构建体。第一个目标将定义特定的氧化脂质配体在激活中的作用 巨噬细胞CD36，确定巨噬细胞中CD36信号通路的分子元素， 表征由CD36诱导的细胞内信号通路，并定义了该机制 CD36与其他血管细胞受体信号通路的交谈，重点是先天的受体 免疫系统和胰岛素受体。第二个目标将定义CD36信号调节的机制 特定的巨噬细胞功能；例如脂蛋白和凋亡细胞摄取，炎症调节 反应和细胞迁移。