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

• 批准号: 9115709
• 负责人: SOTIRIOS TSIMIKAS
• 金额: $ 40.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/9115709
• 关键词: Acetaldehyde; Adverse effects; Affinity; Amino Acids; Antibodies; Apoptotic; Applications Grants; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; 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; Health; Hepatotoxicity; Human; Image; 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; adaptive immunity; adduct; atherogenesis; base; cardiovascular disorder risk; clinical application; cost effective; cost effectiveness; design; extracellular; ferumoxtran; gadolinium oxide; high risk; imaging agent; 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; peptidomimetics; small molecule; specific biomarkers; targeted agent; tool; uptake

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）：本申请旨在生成新型基于磁共振的纳米颗粒，以成像炎症动脉粥样硬化病变中存在的氧化特异性表位。现在有强烈的共识，先天和适应性免疫应答氧化特异性表位导致介导动脉粥样硬化和心血管事件的促炎症反应。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，都支持氧化是动脉粥样硬化病变进展和不稳定的关键表现。这些氧化特异性表位中的一些，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和完全人抗体来检测它们在血管壁中。氧化特异性表位存在于人类动脉粥样硬化病变中，并且在病理定义的易损斑块中特别丰富。我们的拨款提案将侧重于开发氧化特异性的“天然”抗体，存在于种系中