Macrophage Phenotypes and Tissue Repair

项目总结 我的实验室的长期目标是对 组织修复中的炎症反应并开发新的治疗方法 炎症反应，促进组织修复。在过去的15年里，我的主要关注点 巨噬细胞在组织损伤、修复和再生中的作用已有研究。我的 实验室发表的研究结果表明，巨噬细胞在两种皮肤的修复中发挥重要作用。 这些细胞表现出巨大的表型可塑性 引导伤口度过愈合的每一个阶段。我们的数据还表明，巨噬细胞 糖尿病患者的调节失调导致慢性炎症和皮肤创面愈合受损 以及创伤性肌肉损伤的愈合受阻。重要的是，我们已经展示了 靶向巨噬细胞可以诱导炎症的消退和促进愈合。为 例如，我们发现将抗糖尿病药物格列本脲重新用于局部治疗 皮肤伤口愈合的治疗可以用来抑制伤口中的NLRP3炎症小体， 这会导致从破坏性的促炎细胞转变为促进愈合的巨噬细胞 糖尿病小鼠的表型和改善的愈合。我们现在正在获得一个 为我们的新配方指定研究新药，这是向前发展所需的 进入局部格列本脲治疗糖尿病腿部溃疡的I期人体试验。遵循这一模式 从发现到临床试验的管道将是我们未来所有研究的主要目标。 尽管取得了这些进展，但巨噬细胞的可塑性仍有许多需要了解。 在组织修复和调节巨噬细胞功能的因素，包括细胞固有的 以及细胞-外在途径。为此，我的实验室正在研究每个人的贡献 单核/巨噬细胞系对创伤调控的发育阶段 巨噬细胞在皮肤和骨骼肌修复过程中的功能，在正常愈合和 在小鼠和人类中，受损的愈合模型。我的实验室在未来5年的目标是 要利用新开发的单细胞分析技术来确定，使用 无偏见的方法，巨噬细胞在正常和受损期间采用的实际表型 伤口愈合。这一办法将有助于克服在该领域取得进展的重大障碍， 这是广泛使用的有偏见和过于简单化的方法来分类巨噬细胞 活体内的巨噬细胞群，并有可能识别参与 治愈。我们还将使用单细胞分析技术来指导机械实验 阐明参与调控不同基因的转录因子和途径。 巨噬细胞群。随着我们研究的进展，我们计划解决其他重要的 在伤口愈合领域的认识差距，包括伤口病原体在伤口愈合中的作用 (DYS)调节巨噬细胞功能和组织修复。指导我们的总体愿景 方法是通过确定伤口愈合过程中巨噬细胞功能的新调节因子， 我们可以开发新的方法来控制炎症和促进不良疾病的愈合 愈合伤口，在这个过程中，产生一系列候选疗法，以转化为 临床研究。

PROJECT SUMMARY The long term goals of my laboratory are to generate new insights into the role of the inflammatory response in tissue repair and to develop novel therapies that shape the inflammatory response to improve tissue repair. For the past 15 years, the major focus of my research has been the role of macrophages in tissue damage, repair and regeneration. My laboratory has published findings that macrophages play important roles in repair of both skin and skeletal muscle and that these cells display tremendous phenotypic plasticity while helping to guide a wound through each phase of healing. Our data also demonstrate that macrophage dysregulation contributes to chronic inflammation and impaired skin wound healing in diabetes as well as impaired healing of traumatic muscle injuries. Importantly, we have demonstrated and that targeting macrophages can induce resolution of inflammation and improve healing. For example, we have found that repurposing the anti-diabetic drug glyburide into a topical treatment for skin wound healing can be used to inhibit the NLRP3 inflammasome in wounds, which results in a switch from a destructive pro-inflammatory to a pro-healing macrophage phenotype and improved healing in diabetic mice. We are now in the process of obtaining an Investigational New Drug designation for our new formulation that is needed to move forward into a Phase I human trial on topical glyburide for diabetic leg ulcers. Following this model pipeline from discovery to clinical trial will be a primary goal of all our future studies. Despite these advances, much remains to be learned about the plasticity of macrophages during tissue repair and the factors that regulate macrophage function, including cell-intrinsic and cell-extrinsic pathways. To this end, my laboratory is studying the contributions of each developmental stage of the monocyte/macrophage lineage to the regulation of wound macrophage function during repair of skin and skeletal muscle, in both normal healing and impaired healing models, in mice and humans. A goal of my laboratory over the next 5 years is to take advantage of newly developed single cell analysis techniques to determine, using unbiased methods, the actual phenotypes that macrophages adopt during normal and impaired wound healing. This approach will help overcome a significant barrier to progress in the field, which is the widespread use of biased and oversimplistic methods to categorize macrophage populations in vivo, and has potential to identify novel macrophage populations involved in healing. We will also use the single cell analysis techniques to guide mechanistic experiments to elucidate the transcription factors and pathways involved in the regulation of different macrophage populations. As our research progresses, we plan to address additional significant gaps in understanding in the wound healing field, including the role of wound pathogens in the (dys)regulation of macrophage function and tissue repair. The overall vision guiding our approach is that by identifying novel regulators of macrophage function during wound healing, we can develop new approaches to manipulate inflammation and improve healing of poorly healing wounds, and in the process, generate a pipeline of candidate therapies to translate into clinical studies.