Oxidation-specific nanoparticles for imaging atherosclerosis

用于动脉粥样硬化成像的氧化特异性纳米粒子

基本信息

批准号：
8722892
负责人：
SOTIRIOS TSIMIKAS
金额：
$ 39.49万
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：
2013
资助国家：
美国
起止时间：
2013-08-21 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8722892
关键词：
Acetaldehyde Adverse effects Affinity Amino Acids Antibodies Apoptotic Applications Grants Area Arterial Fatty Streak Arteries Atherosclerosis Binding Biological Markers CD36 gene Cardiovascular Diseases Cardiovascular system Cessation of life Characteristics Clinical Clinical Data Consensus Data Detection Development Dextrans Disadvantaged Drug Kinetics Environmental Risk Factor Epidemiologic Studies Epitopes Event Fetus Foam Cells Gadolinium Gadolinium DTPA Germ Lines Hepatotoxicity Human Image Immune response Immune system Immunodominant Epitopes Inflammatory Response Investigation Ions Iron Knowledge Label Laboratories Lead Lesion Libraries Ligand Binding Lipids Lipoproteins Liver Low-Density Lipoproteins Lysine Magnetic Resonance Magnetic Resonance Imaging Malondialdehyde Manganese Measures Mediating Methods Micelles Modeling Molecular Mus Myocardial Infarction Necrosis Oxidative Stress Patients Peptides Phage Display Pharmacodynamics Phospholipids Proteins Research Proposals Role Specificity Stroke Technology Testing Therapeutic Intervention Translating Translations Umbilical Cord Blood Umbilical cord structure V(D)J Recombination adduct atherogenesis base cardiovascular disorder risk clinical application cost effective cost effectiveness design dextran extracellular ferumoxtran gadolinium oxide high risk imaging probe improved iron oxide macrophage macrophage scavenger receptors molecular imaging mouse model nanoparticle neurotoxicity novel novel diagnostics oxidation oxidized lipid oxidized low density lipoprotein particle public health relevance small molecule tool uptake

项目摘要

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.

描述（由申请人提供）：此应用程序打算生成基于磁共振的新型纳米颗粒，以形象发炎的动脉粥样硬化病变中存在的氧化特异性表位。现在有很强的共识，即对氧化特异性表位的先天和适应性免疫反应会导致促炎性反应，介导动脉粥样硬化和心血管事件。大量的实验和临床数据，包括最近的流行病学研究，这些研究具有预测死亡，心肌梗死和中风的氧化特异性生物标志物，这支持氧化，这是动脉粥样硬化病变的进展和不稳定的关键表现。这些氧化特异性表位中的几个（例如氧化的磷脂和丙二醛 - 赖氨酸表位）已在我们的实验室和特定的鼠类中得到很好的特征，并且已经产生了完全人类的抗体，可以在容器壁中检测它们。氧化特异性表位存在于人动脉粥样硬化病变中，并且特别富含病理定义的脆弱斑块。我们的赠款提案将重点介绍生物系中存在的氧化特异性“自然”抗体人类，作为动脉粥样硬化病变中特定特定表位的独特和特定探针。这种方法将主要靶向凋亡和坏死巨噬细胞，氧化脂质以及动脉粥样硬化病变核心的细胞外氧化特异性表位。另外，作为更广泛的模仿t的一部分，在动脉粥样硬化中，我们开发了脂肽或模仿氧化特异性表位，以特异性结合巨噬细胞清道夫受体CD36和SRA。作为这些更基本研究的转化方面，我们将开发这些脂肽和模emotopes，作为靶向活化巨噬细胞上存在的巨噬细胞清除剂受体的分子成像探针。所有3种方法的开发都可以使我们能够确定最佳成像方法，以区分细胞外氧化特异性表位与巨噬细胞清除剂受体的成像，并允许比较确定一个或另一个组合是否会导致最佳成像能力。这将回答有关哪种方法可能最有希望转化为临床领域的重要基本问题。在人类中检测和量化氧化特异性表位的能力将允许检测高风险斑块，并提供工具以允许在各种治疗干预措施后进行监视。