Imaging macrophage subset dynamics in inflammation

R&D 2项目总结 巨噬细胞是存在于所有主要组织中的先天免疫细胞，负责体内平衡。 巨噬细胞感知病原体和其他环境挑战并做出反应，并参与组织 受伤后再进行修复。最近的研究表明巨噬细胞是表观遗传学上显著的可塑性细胞。 响应于源自组织环境的信号而被编程。巨噬细胞的异质性和 通过微环境如何塑造巨噬细胞的表型和功能特性，可塑性是显而易见的 确保巨噬细胞持续适应环境。通常，巨噬细胞被定义为M1 巨噬细胞(经典激活的促炎巨噬细胞)和M2巨噬细胞(交替 激活的组织驻留抗炎巨噬细胞)。M1巨噬细胞是促炎细胞，并具有 在宿主防御炎症和感染中发挥中心作用，而M2巨噬细胞与 对抗炎反应和组织重塑的反应，它们代表了完整的 巨噬细胞激活谱。由于不同表型的巨噬细胞的转化调节 炎症性疾病的发生、发展和终止，跟踪明确定义的 巨噬细胞群在多个器官中持续表达表面标志物以进行询问 它们在炎症性疾病进展和消退过程中的时空分布 恶性肿瘤。基于我们以前的工作和已发表的数据，我们已经确定了趋化因子受体2型 (CCR2)作为M1巨噬细胞的表面生物标志物，CD163作为M2巨噬细胞的生物标志物。我们有 开发了第一个CCR2放射性示踪剂成像炎症动物模型和恶性肿瘤，以及 人类。我们还开发了第一个用于初步评估的CD163放射性示踪剂。在这项提案中，我们计划 进一步提高CCR2的成像效率，彻底评估CD163示踪剂，以确定 炎症性疾病和癌症中M1和M2巨噬细胞的时空分布。因此， 我们提出了与我们的合作项目密切合作的以下3个具体目标。目标1.开发新的 CCR2靶向放射性示踪剂成像M1促炎巨噬细胞。目标2.有针对性地开发CD163 放射性示踪剂成像M2组织驻留巨噬细胞。目的3.验证巨噬细胞特异性放射性示踪剂以检测 炎症性疾病和恶性肿瘤中巨噬细胞的异质性、时空分布。 这些产品和在当前赠款周期中开发的产品也将提供给我们的服务项目。

TR&D 2 Project Summary Macrophages are innate immune cells present in all major tissues and are responsible for homeostasis. Macrophages sense and respond to pathogens and other environmental challenges and participate in tissue repair after injury. Recent research reveals macrophages as remarkably plastic cells that are epigenetically programmed in response to signals originating from the tissue environment. The macrophage heterogeneity and plasticity is evident from how the microenvironment shapes macrophage phenotype and functional identity that ensures ongoing adaption of macrophages to the environment. Typically, macrophages are defined as M1 macrophages (classically activated pro-inflammatory macrophages) and M2 macrophages (alternatively activated tissue-resident anti-inflammatory macrophages). M1 macrophages are pro-inflammatory and have a central role in host defense against inflammation and infection, while M2 macrophages are associated with responses to anti-inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. Since the transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases, it is critical to track the well-defined macrophages populations with constant expression of surface markers across multiple organs to interrogate their temporal and spatial distribution along the progression and regression of inflammatory diseases or malignancies. Based on our previous work and published data, we have identified chemokine receptor type 2 (CCR2) as a surface biomarker for M1 macrophage and CD163 as a biomarker for M2 macrophage. We have developed the first CCR2 radiotracer imaging inflammation in animal models and malignancies, as well as humans. We have also developed the first CD163 radiotracer for initial evaluation. In this proposal, we plan to further improve the imaging efficiency of CCR2 and thoroughly assess CD163 tracers in order to determine the temporal and spatial distribution of M1 and M2 macrophages in inflammatory diseases and cancers. Therefore, we proposal the following 3 specific aims working closely with our Collaborative Projects. Aim 1. Develop new CCR2 targeted radiotracers imaging M1 pro-inflammatory macrophages. Aim 2. Develop CD163 targeted radiotracer imaging M2 tissue resident macrophages. Aim 3. Validate macrophage-specific radiotracers to detect heterogeneity, temporal and spatial distribution of macrophages in inflammatory diseases and malignancies. These products and those developed in the current grant cycle will be provided to our Service Projects as well.