Oxidation-specific nanoparticles for imaging atherosclerosis

描述(申请人提供)：这项申请旨在产生新的基于磁共振的纳米颗粒，以成像存在于炎症的动脉粥样硬化病变中的氧化特异性表位。现在有强烈的共识，即对氧化特异表位的先天和获得性免疫反应会导致促炎反应，从而介导动脉粥样硬化和心血管事件。大量的实验和临床数据，包括最近用氧化特异性生物标志物预测死亡、心肌梗死和中风的流行病学研究，支持氧化作为动脉粥样硬化病变进展和不稳定的关键表现。其中几个氧化特异性表位，如氧化磷脂和丙二醛-赖氨酸表位，已经在我们的实验室中得到了很好的表征，并且已经产生了特异性的小鼠抗体和全人抗体来在血管壁中检测它们。氧化特异性表位存在于人类动脉粥样硬化病变中，在病理定义的脆弱斑块中尤其丰富。我们的拨款计划将专注于开发存在于生殖系中的氧化特异性“天然”抗体。 作为独特和特异的探针，用于成像动脉粥样硬化病变中的氧化特异性表位。这种方法将主要针对存在于凋亡和坏死性巨噬细胞、氧化脂质和动脉粥样硬化病变核心中修饰/氧化的基底蛋白上的细胞外氧化特异性表位。此外，作为在动脉粥样硬化形成中利用先天免疫系统，特别是巨噬细胞清道夫受体知识的更广泛模拟的一部分，我们开发了模拟氧化特异性表位的脂肽或模拟表位，它们与巨噬细胞清道夫受体CD36和SRA特异性结合。作为这些更基础的研究的翻译方面，我们将开发这些脂肽和模拟表位作为针对存在于激活的巨噬细胞上的巨噬细胞清道夫受体的分子成像探针。所有三种方法的发展可能使我们能够确定最佳的成像方法，以区分细胞外氧化特异性表位和巨噬细胞清道夫受体的成像，并允许比较以确定其中之一或两者的组合是否导致最佳成像能力。这将回答重要的基本问题，即这些方法中的哪一种可能是最有希望转化到临床领域的。检测和量化人类氧化特异性表位的能力将允许检测高风险斑块，并提供工具，以便在各种治疗干预之后进行监测。

DESCRIPTION (provided by applicant): This application intends to generate novel magnetic resonance based nanoparticles to image oxidation-specific epitopes present in inflamed atherosclerotic lesions. There is now strong consensus that innate and adaptive immune responses to oxidation-specific epitopes lead to pro- inflammatory responses that mediate atherosclerosis and cardiovascular events. A wealth of experimental and clinical data, including recent epidemiological studies with oxidation-specific biomarkers predicting death, myocardial infarction and stroke, supports oxidation as a key manifestation of both the progression and destabilization of atherosclerotic lesions. Several of these oxidation-specific epitopes, such as oxidized phospholipids and malondialdehyde-lysine epitopes, have been well characterized in our laboratory and specific murine and fully human antibodies have been generated to detect them in the vessel wall. Oxidation-specific epitopes are present in human atherosclerotic lesions, and are particularly enriched in pathologically defined vulnerable plaques. Our grant proposal will focus on developing oxidation-specific "natural" antibodies, present in the germ line of humans, as unique and specific probes to image oxidation specific epitopes in atherosclerotic lesions. This approach would predominantly target extracellular oxidation-specific epitopes present on apoptotic and necrotic macrophages, oxidized lipids and, modified/oxidized basement proteins in the atherosclerotic lesion core. In addition, as part of a broader imitative t harness the knowledge of the innate immune system, and specifically macrophage scavenger receptors, in atherogenesis, we have developed lipopeptides or mimotopes modeling oxidation specific epitopes that bind specifically to macrophage scavenger receptors CD36 and SRA. As a translational aspect of these more basic investigations, we will develop these lipopeptides and mimotopes as molecular imaging probes targeting macrophage scavenger receptors present on activated macrophages. Development of all 3 approaches may allow us to determine optimal imaging approaches to differentiate imaging of extracellular oxidation-specific epitopes versus macrophage scavenger receptors, and allow comparisons to determine if one or the other or a combination results in optimal imaging capability. This will answer important fundamental questions about which of these approaches may be most promising to translate to the clinical arena. The ability to detect and quantify oxidation-specific epitopes in humans will allow detection of high risk plaques and provide the tools to allow surveillance following a variety of therapeutic interventions.