Early Forms of Oxidized LDL, TLRs and Atherosclerosis

低密度脂蛋白的氧化修饰即使不是强制性的，也是调节低密度脂蛋白致动脉粥样硬化的重要步骤。 许多病理条件和环境因素促进低密度脂蛋白的氧化，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)。除了已建立的存在之外 关于动脉粥样硬化病变中氧化低密度脂蛋白的研究，最近的报告发现，甚至在血液中也存在早期氧化形式的低密度脂蛋白 看起来健康的人，以及患有心血管疾病的人的水平升高。这项建议 我将检验我的假设，即MmLDL通过调节 Toll样受体(TLR)信号转导。这一假设得到了我们最近发表的研究结果的支持 这种低密度脂蛋白，但不是被广泛氧化的低密度脂蛋白，与CD14结合，这个复合体激活TLR4， 导致细胞骨架重排和促炎信号和细胞因子的表达。在……里面 此外，我们的初步数据表明，MmLDL通过以下方式增加内毒素诱导的细胞因子的分泌 巨噬细胞体外培养。CD14和TLR4是感知细菌脂蛋白的关键先天免疫受体。 通过CD14/TLR4的MMLDL4信号的存在提示免疫反应趋同于 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)测试假设，即MMLDL4诱导TLR4与其他受体在 巨噬细胞的表面，从而启动独特的细胞内信号级联反应。2)测试 一种假说认为，一组独特的促炎基因表达和分泌对mm-LDL是一种 TLR4依赖和独立信号通路之间串扰的结果。3)测试 一种假设：MmLDL增强内毒素和其他TLR诱导的促炎基因表达 炎症动物模型中的配体。4)检验MmLDL促进TLR依赖的假设 动脉粥样硬化病变中的炎症。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作用机制及更好的理解 特殊的微生物病原体会增加动脉粥样硬化并发症的风险。因为被氧化的 这些研究表明，一般情况下，低密度脂蛋白中的部分成分很可能是氧化膜的常见成分 可能具有普遍的重要性。

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.