Early Forms of Oxidized LDL, TLRs and Atherosclerosis

氧化 LDL、TLR 和动脉粥样硬化的早期形式

• 批准号: 7216749
• 负责人: Yury Miller
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216749
• 关键词: Animal Model; Arterial Fatty Streak; Atherosclerosis; Autoantigens; Binding; Biological; Blood; CD14 gene; Cardiovascular Diseases; Chronic; Complex; Condition; Cultured Cells; Cytokine Signaling; DNA Sequence Rearrangement; Data; Development; Environmental Risk Factor; Event; F-Actin; Gene Expression; Genes; Immune response; Immunohistochemistry; Immunologic Receptors; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Lesion; Ligands; Lipids; Lipopolysaccharides; Lipoprotein (a); Lipoprotein (a-); Lipoprotein Binding; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Macrophage Activation; Mediating; Membrane; Minimally modified Low Density Lipoprotein; Modification; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Plasma; Proteins; Publishing; Receptor Activation; Receptor Signaling; Reporting; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Staining method; Stains; Surface; Testing; Time; Toll-like receptors; concept; cytokine; in vivo; laser capture microdissection; macrophage; microbial; oxidation; oxidized low density lipoprotein; pathogen; receptor; response; toll-like receptor 4

DESCRIPTION (provided by applicant): Oxidative modification of LDL is an important, if not obligatory, step that mediates the atherogenicity of LDL. Many pathological conditions and environmental factors promote LDL oxidation, especially formation of early forms of oxidized LDL, termed minimally modified LDL (mmLDL). In addition to established presence of oxidized LDL in atherosclerotic lesions, recent reports find early oxidized forms of LDL even in the blood of apparently healthy individuals, and elevated levels in people with cardiovascular disease. This proposal will examine my hypothesis that mmLDL promotes inflammation in atherosclerotic lesions via modulation of Toll-like receptor (TLR) signaling. This hypothesis has been supported by our recently published findings that mmLDL, but not extensively oxidized LDL, binds to CD14 and that this complex activates TLR4, resulting in cytoskeletal rearrangements and pro-inflammatory signaling and cytokine expression. In addition, our preliminary data demonstrate that mmLDL augments LPS-induced cytokine secretion by macrophages in vitro. CD14 and TLR4 are crucial innate immune receptors that sense bacterial LPS. The existence of mmLDL signaling through CD14/TLR4 suggests convergence of immune responses to oxidation-specific self-antigens and to microbial pathogens. I propose the following Specific Aims for this project: 1) To test the hypothesis that mmLDL induces specific clustering of TLR4 with other receptors on the surface of macrophages, thereby initiating a unique intracellular signaling cascade. 2) To test the hypothesis that a unique set of pro-inflammatory genes expressed and secreted in response to mmLDL is a result of a crosstalk between TLR4-dependent and independent signaling pathways. 3) To test the hypothesis that mmLDL augments pro-inflammatory gene expression induced by LPS and other TLR ligands in animal models of inflammation. 4) To test the hypothesis that mmLDL promotes TLR-dependent inflammation in atherosclerotic lesions. Further development of my hypothesis will help elucidate mechanisms of chronic inflammation in development of atherosclerosis and better understand how particular microbial pathogens increase the risk of atherosclerotic complications. Because the oxidized moieties in mmLDL are likely to be common components of oxidized membranes in general, these studies are likely to have generalized importance.

描述（由申请方提供）：LDL的氧化修饰是介导LDL致动脉粥样硬化性的重要（如果不是强制性的）步骤。许多病理条件和环境因素促进LDL氧化，特别是氧化LDL的早期形式的形成，称为最小修饰的LDL（mmLDL）。除了在动脉粥样硬化病变中存在氧化LDL外，最近的报告发现，即使在明显健康的个体的血液中也存在早期氧化形式的LDL，并且在患有心血管疾病的人中水平升高。该提案将检验我的假设，即mmLDL通过调节Toll样受体（TLR）信号促进动脉粥样硬化病变中的炎症。我们最近发表的研究结果支持了这一假设，即mmLDL而不是广泛氧化的LDL与CD 14结合，并且该复合物激活TLR 4，导致细胞骨架重排和促炎信号传导和细胞因子表达。此外，我们的初步数据表明，mmLDL增强LPS诱导的细胞因子分泌的巨噬细胞在体外。CD 14和TLR 4是感受细菌LPS的重要先天性免疫受体。通过CD 14/TLR 4的mmLDL信号传导的存在表明对氧化特异性自身抗原和微生物病原体的免疫应答的收敛。本课题的具体目的是：1）验证mmLDL诱导TLR 4与巨噬细胞表面其他受体特异性聚集，从而启动独特的细胞内信号级联反应的假设。2)为了检验以下假设：在对mmLDL的应答中表达和分泌的一组独特的促炎基因是TLR 4依赖性和独立信号通路之间串扰的结果。3)在动物炎症模型中，检验mmLDL增强LPS和其他TLR配体诱导的促炎基因表达的假设。4)检验mmLDL促进动脉粥样硬化病变中TLR依赖性炎症的假设。我的假说的进一步发展将有助于阐明动脉粥样硬化发展中的慢性炎症机制，并更好地了解特定的微生物病原体如何增加动脉粥样硬化并发症的风险。由于mmLDL中的氧化部分通常可能是氧化膜的常见组分，因此这些研究可能具有普遍的重要性。