Translational imaging and nanomedicine in inflammatory atherosclerosis

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SUMMARY Thrombotic complications in atherosclerosis are decisively determined by macrophage inflammation. In preclinical disease models, atherosclerosis is substantially diminished if macrophage numbers are decreased. Recent work from our Program Project's investigators has shown that real life stressors aggravate atherosclerosis in mice. In patients, psychosocial stress is a well-recognized risk factor for inflammatory diseases, including atherosclerosis (odds ratio 2.1 for myocardial infarction). Therefore, in both animal models and human subjects, an unmet need hinders our understanding of how risk factors for ischemic events, such as psychosocial stress or organ ischemia, accelerate atherosclerosis. We and others recently described that macrophage dynamics in atherosclerotic plaque depend on recruitment (R) of monocytes from the spleen and bone marrow, but can also arise from local proliferation (P), especially in established atherosclerosis. Thus, to understand the processes leading to increased inflammation in atherosclerotic plaque, i.e. progression of atherosclerosis, it is essential to measure systemic supply parameters, including monocyte production in hematopoietic tissues (spleen, bone marrow), recruitment of cells into the plaque, and local cell proliferation. Conversely, cell death and exit (E) may decrease the overall macrophage number in tissue. Currently, we lack non-invasive means of measuring macrophage recruitment, proliferation or exit (R/P/E) in mice and patients. This is a considerable hurdle for gaining a better understanding of basic atherosclerosis biology and for developing new therapeutic strategies targeted to immune cells. Once identified, these pathways could be tested as new therapeutic targets. In the clinical realm, the lack of non- invasive tools that measure R/P/E prevents us from understanding whether or not processes discovered in basic research translate to human patients. In Project 2 we propose to develop, validate, and translate innovative positron emission tomography combined with magnetic resonance imaging (PET/MRI) methods for both preclinical and clinical measurement of plaque macrophage dynamics. In Aim 1, we will develop integrated PET/MRI to study macrophage recruitment to lesions, macrophage proliferation, and macrophage exit by creatively combining existing imaging agents in atherosclerotic mice subjected to real-life stressors. In Aim 2, we will generate an immune cell-directed nanoparticle library screen and use 89Zr radiolabeling to develop new recruitment and proliferation (R/P) imaging agents. In Aim 3, we will test clinically-viable PET/MRI protocols in atherosclerotic rabbits and translate protocols for clinical imaging in human patients, interfacing with Project 3.