Translational imaging and nanomedicine in inflammatory atherosclerosis

炎症性动脉粥样硬化的转化成像和纳米医学

• 批准号: 10116448
• 负责人: Willem Mulder
• 金额: $ 68.03万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116448
• 关键词: Address; Animal Model; Animals; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Autoradiography; Basic Science; Biology; Bone Marrow; Cardiovascular system; Carotid Artery Plaques; Cell Death; Cell Proliferation; Cells; Clinical; Clinical Protocols; Clinical Trials; Companions; Coronary; Data; Dextrans; Disease; Disease model; Endarterectomy; Ensure; Event; Exposure to; Extracellular Matrix; Flow Cytometry; Fluorescent Dyes; Hematopoietic stem cells; Histologic; Human; Hybrids; Image; Immune; Immunology; Inflammation; Inflammatory; Ischemia; Label; Lesion; Libraries; Life; Ligation; Magnetic Resonance Imaging; Measurement; Measures; Methods; Molecular; Mus; Myocardial Infarction; Odds Ratio; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Parabiosis; Pathway interactions; Patient Schedules; Patients; Peptide Hydrolases; Positron-Emission Tomography; Process; Production; Proliferating; Protocols documentation; Psychosocial Stress; Publishing; Radiolabeled; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Specificity; Specimen; Spleen; Stress; Systems Biology; Techniques; Testing; Tissues; Translating; Vascular Cell Adhesion Molecule-1; Work; cardiovascular imaging; clinical imaging; contrast enhanced; cost; cytokine; ferumoxytol; hematopoietic tissue; human subject; imaging agent; imaging modality; imaging probe; in vivo; in vivo imaging; innovation; iron oxide; iron oxide nanoparticle; macrophage; monocyte; mouse model; nanomaterials; nanomedicine; nanoparticle; new therapeutic target; next generation; novel; novel therapeutic intervention; pre-clinical; prevent; progenitor; programs; recruit; stressor; synergism; targeted treatment; therapeutic target; thrombotic complications; tomography; tool; uptake

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.

概括 动脉粥样硬化的血栓并发症是由巨噬细胞炎症决定性决定的。在 在临床前疾病模型中，如果巨噬细胞数量减少，动脉粥样硬化就会大大减少。 我们的项目研究人员最近的工作表明，现实生活中的压力源会加剧 小鼠动脉粥样硬化。在患者中，社会心理压力是公认的炎症风险因素 疾病，包括动脉粥样硬化（心肌梗塞的比值比为 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事件风险因素的理解，例如 由于心理压力或器官缺血，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取决于 来自脾脏和骨髓的单核细胞募集（R），但也可能由局部增殖引起 (P)，特别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，有必要测量全身性的 供应参数，包括造血组织（脾脏、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 组织中巨噬细胞的总数。 目前，我们缺乏测量巨噬细胞招募、增殖或退出的非侵入性方法 (R/P/E) 在小鼠和患者中。这对于更好地理解基本知识来说是一个相当大的障碍。 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 确定后，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是否在 基础研究转化为人类患者。 在项目 2 中，我们建议开发、验证和转化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 PET/MRI 来研究巨噬细胞 通过创造性地结合现有的巨噬细胞募集到病灶、巨噬细胞增殖和巨噬细胞退出 在承受现实生活压力的动脉粥样硬化小鼠中使用显像剂。在目标 2 中，我们将生成一个免疫 细胞定向纳米颗粒库筛选并使用 89Zr 放射性标记开发新的招募和 增殖（R/P）显像剂。在目标 3 中，我们将测试临床上可行的动脉粥样硬化 PET/MRI 方案 兔子并翻译人类患者临床成像的协议，与项目 3 接口。