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: 7839765
• 负责人: Yury Miller
• 金额: $ 23.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7839765
• 关键词: Animal Model; Arterial Fatty Streak; Atherosclerosis; Autoantigens; Binding; Biological; Blood; CD14 gene; Cardiovascular Diseases; Cell Culture Techniques; Chronic; Complex; 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 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; cytokine; in vivo; laser capture microdissection; macrophage; microbial; oxidation; oxidized low density lipoprotein; pathogen; receptor; response; toll-like receptor 4

Oxidative modification of LDL is an important, if not obligatory, step that mediates the atherogenicity ofLDL. 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 cardiovasculardisease. 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.

LDL 的氧化修饰是介导 LDL 致动脉粥样硬化性的重要步骤（如果不是强制性的）。 许多病理条件和环境因素都会促进 LDL 氧化，特别是形成 氧化低密度脂蛋白的早期形式，称为最小修饰低密度脂蛋白（mmLDL）。除了既定的存在 最近的报告发现，即使在血液中也存在早期氧化形式的 LDL 表面健康的人的水平，以及患有心血管疾病的人的水平升高。这个提议 将检验我的假设，即 mmLDL 通过调节 Toll 样受体 (TLR) 信号传导。我们最近发表的研究结果支持了这一假设 mmLDL（但不是广泛氧化的 LDL）与 CD14 结合，并且该复合物激活 TLR4， 导致细胞骨架重排、促炎信号传导和细胞因子表达。在 此外，我们的初步数据表明，mmLDL 通过以下方式增强 LPS 诱导的细胞因子分泌： 体外巨噬细胞。 CD14 和 TLR4 是感知细菌 LPS 的重要先天免疫受体。 mmLDL 通过 CD14/TLR4 信号传导的存在表明免疫反应趋于一致 氧化特异性自身抗原和微生物病原体。为此，我提出以下具体目标 项目：1) 检验 mmLDL 诱导 TLR4 与其他受体特异性聚集的假设 巨噬细胞表面，从而启动独特的细胞内信号级联反应。 2) 测试 假设一组独特的促炎基因响应 mmLDL 表达和分泌，是一种 TLR4 依赖性和独立信号通路之间串扰的结果。 3）测试 mmLDL 增强 LPS 和其他 TLR 诱导的促炎基因表达的假设 炎症动物模型中的配体。 4) 检验 mmLDL 促进 TLR 依赖性的假设 动脉粥样硬化病变中的炎症。我的假设的进一步发展将有助于阐明 慢性炎症在动脉粥样硬化发展中的机制，并更好地了解如何 特定的微生物病原体会增加动脉粥样硬化并发症的风险。因为氧化了 mmLDL 中的部分通常可能是氧化膜的常见成分，这些研究 可能具有普遍重要性。