Translational imaging and nanomedicine in inflammatory atherosclerosis

摘要 动脉粥样硬化的血栓并发症由巨噬细胞炎症决定。在……里面 在临床前疾病模型中，如果巨噬细胞数量减少，动脉粥样硬化就会显著减轻。 我们项目调查人员最近的研究表明，现实生活中的压力会加剧 小鼠的动脉粥样硬化。在患者中，心理社会压力是公认的炎症危险因素。 疾病，包括动脉粥样硬化(心肌梗死的优势比为2.1)。因此，在这两种动物模型中 和人类受试者，未得到满足的需求阻碍了我们对缺血事件的风险因素的理解，如 由于心理社会压力或器官缺血，会加速动脉粥样硬化。 我们和其他人最近描述了动脉粥样硬化斑块中巨噬细胞的动力学依赖于 脾和骨髓中单核细胞的募集(R)，但也可由局部增殖引起 (P)，特别是在已有的动脉粥样硬化中。因此，要了解导致增长的过程 动脉粥样硬化斑块中的炎症，即动脉粥样硬化的进展，测量系统是必要的 供应参数，包括造血组织(脾、骨髓)中单核细胞的产生、募集 进入斑块的细胞，以及局部细胞的增殖。相反，细胞死亡和退出(E)可能会降低 组织内巨噬细胞总数。 目前，我们缺乏测量巨噬细胞募集、增殖或退出的非侵入性手段。 (r/P/E)。这是更好地理解基本知识的一个相当大的障碍 动脉粥样硬化生物学和开发针对免疫细胞的新治疗策略。一次 一旦确定，这些通路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的侵入性工具阻止我们了解在 基础研究也适用于人类患者。 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 结合磁共振成像(PET/MRI)方法进行临床前和临床测量 斑块巨噬细胞动力学。在目标1中，我们将开发集成的PET/MRI来研究巨噬细胞 通过创造性地结合现有的病变、巨噬细胞增殖和巨噬细胞退出 动脉粥样硬化小鼠在现实生活应激源作用下的显像剂。在目标2中，我们将产生一种免疫 细胞定向纳米粒子库的筛选和使用89Zr放射性标记开发新的募集和 增殖(R/P)显像剂。在目标3中，我们将在动脉粥样硬化中测试临床可行的PET/MRI方案 用于人类患者临床成像的兔子和翻译方案，与项目3接口。

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.