Translational imaging and nanomedicine in inflammatory atherosclerosis

总结 动脉粥样硬化中的血栓并发症由巨噬细胞炎症决定。在 在临床前疾病模型中，如果巨噬细胞数目减少，则动脉粥样硬化显著减少。 我们项目的调查人员最近的工作表明，真实的生活压力源会加剧 小鼠动脉粥样硬化。在患者中，心理社会压力是炎症性疾病的公认危险因素。 疾病，包括动脉粥样硬化（心肌梗死的比值比2.1）。因此，在两种动物模型中， 和人类受试者，未满足的需求阻碍了我们对缺血性事件风险因素的理解， 如心理社会压力或器官缺血，加速动脉粥样硬化。 我们和其他人最近描述了动脉粥样硬化斑块中的巨噬细胞动力学依赖于 从脾和骨髓募集（R）单核细胞，但也可由局部增殖引起 (P)尤其是在已形成的动脉粥样硬化中。因此，要了解导致增加的过程 动脉粥样硬化斑块中的炎症，即动脉粥样硬化的进展，测量全身性 供应参数，包括造血组织（脾、骨髓）中单核细胞的产生、募集 细胞进入斑块，局部细胞增殖。相反，细胞死亡和退出（E）可能会降低细胞的存活率。 组织中的巨噬细胞总数。 目前，我们缺乏测量巨噬细胞募集、增殖或退出的非侵入性方法 （R/P/E）。这对于更好地理解基本的 动脉粥样硬化生物学和开发靶向免疫细胞的新治疗策略。一旦 这些途径可以作为新的治疗靶点进行测试。在临床领域，缺乏非- 测量R/P/E的侵入性工具使我们无法了解在 基础研究转化为人类患者。 在项目2中，我们建议开发，验证和翻译创新的正电子发射断层扫描技术 结合磁共振成像（PET/MRI）方法进行临床前和临床测量 噬菌斑巨噬细胞动力学。目的一：开发PET/MRI一体化系统，用于巨噬细胞的研究 通过创造性地结合现有的细胞因子， 成像剂在动脉粥样硬化小鼠经受现实生活中的压力。在目标2中，我们将生成免疫 细胞定向纳米颗粒库筛选和使用89 Zr放射性标记来开发新的募集和 增殖（R/P）显像剂。在目标3中，我们将测试临床可行的PET/MRI方案， 兔子和翻译协议的临床成像在人类患者，接口与项目3。

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.