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Early Forms of Oxidized LDL, TLRs and Atherosclerosis

氧化 LDL、TLR 和动脉粥样硬化的早期形式

基本信息

批准号：
7789573
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
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7789573
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

项目摘要

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，如果不是必须的话。许多病理条件和环境因素促进LDL氧化，特别是形成氧化LDL的早期形式，称为最小修饰LDL（mmLDL）。除了现有的存在外，氧化LDL在动脉粥样硬化病变，最近的报告发现，早期氧化形式的LDL，甚至在血液中在表面上健康的个体中，以及在心血管疾病患者中的升高水平。这项建议我将检验我的假设，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，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。在此外，我们的初步数据表明，mmLDL增加LPS诱导的细胞因子分泌，体外巨噬细胞。CD 14和TLR 4是感知细菌LPS的关键先天免疫受体。通过CD 14/TLR 4的mmLDL信号传导的存在表明免疫应答的收敛性，氧化特异性自身抗原和微生物病原体。我为此提出以下具体目标项目：1）为了验证mmLDL诱导TLR 4与其他受体特异性聚集的假设，巨噬细胞的表面，从而启动一个独特的细胞内信号级联。2)测试一个假设是，一组独特的促炎基因在对mmLDL的反应中表达和分泌，这是TLR 4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)为了检验mmLDL促进TLR依赖性动脉粥样硬化病变的炎症。进一步发展我的假设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增加动脉粥样硬化并发症的风险。因为氧化的一般来说，mmLDL中的部分可能是氧化膜的常见成分，这些研究可能具有普遍的重要性。