Imaging macrophage subset dynamics in inflammation

TR&D 2项目摘要 巨噬细胞是存在于所有主要组织中的先天性免疫细胞，负责体内平衡。 巨噬细胞感知并响应病原体和其他环境挑战， 损伤后修复。最近的研究表明，巨噬细胞是一种非常可塑的细胞， 响应于源自组织环境的信号而被编程。巨噬细胞异质性和 可塑性从微环境如何塑造巨噬细胞表型和功能特性是显而易见的， 确保巨噬细胞持续适应环境。通常，巨噬细胞定义为M1 巨噬细胞（经典活化的促炎巨噬细胞）和M2巨噬细胞（替代地 活化的组织驻留抗炎巨噬细胞）。M1巨噬细胞是促炎性的， 在宿主防御炎症和感染中起中心作用，而M2巨噬细胞与 对抗炎反应和组织重塑的反应，它们代表了完整的两个终端 巨噬细胞活化谱。由于巨噬细胞的不同表型的转化调节 炎症性疾病的发生、发展和停止，关键是要跟踪明确的 在多个器官中具有恒定表达的表面标志物的巨噬细胞群体， 它们的时间和空间分布沿着炎症性疾病的进展和消退，或 恶性肿瘤。基于我们以前的工作和发表的数据，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和CD163作为M2巨噬细胞的生物标志物。我们有 开发了第一个CCR2放射性示踪剂成像动物模型和恶性肿瘤炎症，以及 人类我们还开发了第一种用于初步评估的CD 163放射性示踪剂。在这份提案中，我们计划 进一步提高CCR2的成像效率，并彻底评估CD163示踪剂，以确定 M1和M2巨噬细胞在炎性疾病和癌症中时空分布。因此，我们认为， 我们提出以下3个具体目标与我们的合作项目密切合作。目标1。开发新 CCR2靶向放射性示踪剂成像M1促炎性巨噬细胞。目标2.开发CD163靶向 放射性示踪剂成像M2组织驻留巨噬细胞。目标3。巨噬细胞特异性放射性示踪剂检测 炎症性疾病和恶性肿瘤中巨噬细胞的异质性、时间和空间分布。 这些产品以及在当前资助周期内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.