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INFLAMMATORY CELL SIGNALING BY CD36

CD36 的炎症细胞信号传导

基本信息

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
项目类别：
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

项目摘要

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.

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