Tracking M2-Like Macrophages in Cardiopulmonary Diseases by Magnetic Resonance Imaging

项目摘要 我目前是马萨诸塞州总医院和哈佛大学放射科的讲师 医学院我的长期职业目标是成为生物标记成像领域的独立研究者 开发和翻译，以更好地了解和诊断心肺疾病中的炎症。我 将在Simches研究中心（CSB）的系统生物学中心进行拟议的研究， MGH的海军基地校园在John Chen博士，Umar Mahmood和Mikael Pittet的指导下， 在显像剂开发、心血管成像开发和先天性 免疫学Filip Swirski博士和Guangbin Dong博士将加入咨询委员会，提供建议， 指导除了指导和咨询会议，我计划加深和扩大我的知识 并通过参加生物医学成像、免疫学和心肺病理生理学培训， 在哈佛医学院和哈佛社区举办正式课程、讲习班和研讨会， 参加相关领域的会议。这个K25补助金将为我提供培训和经验， 这是成长为生物医学成像研究独立调查员所必需的。 研究综述 两种主要的活化巨噬细胞表型，经典活化巨噬细胞（M1），其是促细胞增殖的。 炎性和杀菌性，以及交替激活的巨噬细胞（M2），其是抗炎的， 具有修复作用，在包括伤口愈合、心肌梗塞和癌症在内的各种疾病中发挥关键作用。 巨噬细胞表型和功能的重要性使其成为有吸引力的诊断和治疗 目标然而，由于这些细胞的异质性和复杂性，这些细胞的体内检测仍然具有挑战性 巨噬细胞的表型。非常需要有效和特异性的体内工具。很少成像 已经开发了解决这个问题的方法。甘露糖受体是M2受体的一个公认的标志物。 如巨噬细胞，其识别并结合到末端甘露糖、岩藻糖或N-乙酰葡糖胺上， 病原性病毒、细菌或真菌的表面。我们假设通过筛选和优化甘露糖- 基于配体靶向甘露糖受体，我们将确定一个高效的磁共振成像 (MRI)可区分M2样巨噬细胞和M1样巨噬细胞的探针。因此，这一目标 建议是1）开发靶向甘露糖受体的MRI探针以检测M2样巨噬细胞， 在伤口愈合的小鼠模型中验证它，和2）应用最佳探针纵向追踪M2样 巨噬细胞在心肌梗死和肺癌的小鼠模型，与最终目标， 在未来的研究中将这项技术转化为人类使用。 !

Project Summary I am currently an Instructor in the Department of Radiology at Massachusetts General Hospital and Harvard Medical School. My long-term career goal is to become an independent investigator in biomarker imaging development and translation to better understand and diagnose inflammation in cardiopulmonary diseases. I will perform the proposed study at the Center for Systems Biology at the Simches Research Center (CSB) and MGH’s Navy Yard campus under the mentorship of Drs. John Chen, Umar Mahmood and Mikael Pittet, who have complementary expertise in imaging agent development, cardiovascular imaging development and innate immunology. Drs. Filip Swirski and Guangbin Dong will join on the advisory committee to provide advice and guidance. In addition to the mentorship and advisory meetings, I plan to deepen and broaden my knowledge and training in biomedical imaging, immunology and cardiopulmonary pathophysiology through attending formal courses, workshops and seminars at Harvard Medical School and the Harvard community as well as attending relevant conferences in the fields. This K25 grant will provide me with the training and experience necessary to grow into an independent investigator in biomedical imaging research. Research Summary Two major activated macrophage phenotypes, classically activated macrophages (M1), which are pro- inflammatory and bactericidal, and alternatively activated macrophages (M2) which, are anti-inflammatory and reparative, play critical roles in various diseases including wound healing, myocardial infarction and cancer. The importance of macrophage phenotypes and function make them an attractive diagnostic and therapeutic target. However, in vivo detection of these cells remains challenging due to the heterogeneity and complexity of the macrophage phenotypes. Efficacious and specific in vivo tools are greatly needed. Few imaging methods have been developed to tackle this issue. Mannose receptors are a well-established marker for M2- like macrophages, which recognize and bind to terminal mannose, fucose or N-acetylglucosamine on the surface of pathogenic viruses, bacteria or fungi. We hypothesize that by screening and optimizing mannose- based ligands targeting the mannose receptor we will identify a highly efficacious magnetic resonance imaging (MRI) probe that can differentiate M2-like macrophages from M1-like macrophages. Therefore, the goals of this proposal are 1) to develop an MRI probe targeting mannose receptors to detect M2-like macrophages and validate it in a mouse model of wound healing, and 2) to apply the optimal probe to longitudinally track M2-like macrophages in mouse models of myocardial infarction and lung carcinoma, with the ultimate goal of translating this technology for human use in a future study. !