? The overall goal of this proposal is to image inflammation in atherosclerosis by developing and testing novel activatable MR imaging agents that can sense myeloperoxidase (MPO) activity in atheromata. Emerging evidence suggests that activated macrophages secrete various enzymes that mediate inflammation in atherosclerosis, and that MPO in particular may be indicative of high-risk (""""""""vulnerable"""""""") lesions. A recent clinical trial has further shown that elevated MPO levels strongly predict adverse cardiovascular outcomes in patients with chest pain. It is therefore hypothesized that imaging of local MPO activity will be useful in identifying vulnerable atherosclerotic lesions. ? ? We have recently described two novel approaches for imaging peroxidases using either low molecular weight amplifiable paramagnetic substrates or superparamagnetic enzyme pseudosubstrates. The latter method is based on magnetic relaxation switching (MRSW) a phenomenon that occurs when magnetic nanoparticles are brought into close contact to each other (R2 increase of 4-6 fold with negligible R1 change). These activatable, """"""""smart"""""""" agents harness enzyme mediated amplification strategies and can be used to quantitatively measure enzyme activity and inhibition by MR imaging. The current proposal represents an effort to integrate investigators with different expertises to develop, implement and validate the larger field of enzyme imaging in atherosclerosis. Together, the team will translate basic results into new methodologies for in vivo MR imaging. The ultimate goal of this research is to develop clinically useful imaging tools for the molecular assessment of atherosclerosis in vivo, which are currently limited. ? ? ?
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