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.
This research proposal is intended develop novel oxidation- specific imaging probes to image atherosclerotic lesions in patients with cardiovascular disease. This project will determine whether natural antibodies, lipopeptides and mimotopes, small peptides mimicking oxidation-specific epitopes, can be used for magnetic resonance imaging of macrophage-rich atherosclerotic lesions. These molecular imaging probes may provide novel diagnostic tools aimed at detecting atherosclerotic lesions, which reflects an unmet need in identifying and treating patients at risk for cardiovascular disease and events.
|Briley-Saebo, Karen; Yeang, Calvin; Witztum, Joseph L et al. (2014) Imaging of oxidation-specific epitopes with targeted nanoparticles to detect high-risk atherosclerotic lesions: progress and future directions. J Cardiovasc Transl Res 7:719-36|
|Willeit, Peter; Kiechl, Stefan; Kronenberg, Florian et al. (2014) Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 64:851-60|