Deciphering Macrophage Phenotype and Function in Disc Herniation and associated Back/leg Pain

项目摘要 椎间盘突出症是背痛/腿痛的主要原因，估计有80%的人患有这种疾病。 每年仅在美国就花费1000亿美元。椎间盘突出症及其相关疼痛的治疗选择有 非常有限，主要是由于对病理过程的了解不足。目前的研究表明， 炎症是椎间盘突出后急性和慢性阶段背痛/腿痛的关键因素。别人 并且我们发现巨噬细胞是椎间盘疝部位的主要浸润细胞。巨噬 可能在椎间盘突出的不同阶段发挥不同的作用，具有组织和疾病阶段特异性表型 这是因为它们对微环境线索的反应具有显著的可塑性和敏感性。我们的初步数据 显示在椎间盘疝部位浸润的混合巨噬细胞群， 巨噬细胞减少局部炎症。然而，我们的知识的动态表型和功能的 椎间盘突出中浸润的巨噬细胞仍然很少。我们的核心假设是 巨噬细胞亚群在不同阶段促进椎间盘突出的进展， 巨噬细胞的调节将减轻炎症诱导的疼痛并恢复椎间盘内稳态。我们 本R 01的目的是更好地表征巨噬细胞表型、功能和巨噬细胞盘 椎间盘突出和疼痛的机械水平，这有利于我们的长期目标， 用于椎间盘突出症和相关背痛/腿痛的疾病改善疗法。成功完成本 该项目将显著推进我们对巨噬细胞在椎间盘突出中功能的理解， 为未来的治疗发展奠定基础，例如选择性巨噬细胞靶向免疫调节 战略

Project Summary Intervertebral disc herniation is a major cause of back/leg pain, which affects 80% of people with an estimated annual cost of $100 billion in the U.S. alone. Treatment options for disc herniation and its associated pain are very limited, largely due to insufficient understanding of pathological processes. Current research indicates that inflammation is a key contributor to back/leg pain after disc herniation in both acute and chronic phases. Others and we have found that macrophages are the predominant infiltrated cells at disc hernia sites. Macrophages may play distinct roles in various phases of disc herniation with tissue- and disease stage-specific phenotypes due to their remarkable plasticity and sensitivity in response to microenvironment cues. Our preliminary data revealed a mixed population of macrophages infiltrated at disc hernia sites and transiently depletion of macrophages reduced local inflammation. However, our knowledge of dynamic phenotypes and functions of infiltrated macrophages in disc herniation remains scarce. Our central hypothesis is that specific subpopulations of macrophages contribute to the progression of disc herniation at different stages and that modulation of macrophages will alleviate inflammation-induced pain and restore disc homeostasis. Our objective of this R01 is to better characterizing macrophage phenotypes, functions, and macrophage-disc crosstalk in disc herniation and pain at a mechanistic level, which facilitates our long-term goal to develop disease-modifying therapies for disc herniation and associated back/leg pain. Successful completion of this project will significantly advance our understanding of macrophage functions in disc herniation and lay a solid foundation for future therapeutic development, such as a selectively macrophage-targeted immunomodulation strategy.