Macrophage Heterogeneity after Spinal Cord Injury

脊髓损伤后巨噬细胞异质性

• 批准号: 6891640
• 负责人: PHILLIP G POPOVICH
• 金额: $ 34.57万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-05 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891640
• 关键词: cell adhesion molecules; cell population study; cell proliferation; cytokine receptors; gene expression profiling; immunogenetics; inflammation; laboratory mouse; laboratory rat; laser capture microdissection; leukocyte activation /transformation; macrophage; microarray technology; microglia; nervous system regeneration; neurotrophic factors; spinal cord injury; toll like receptor

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) triggers a neuroinflammatory reaction that can aggravate tissue injury (e.g., neuronal death, axonal injury, demyelination) and promote repair (e.g., axon regeneration, remyelination, revascularization). The cellular and molecular mechanisms that underlie this functional dichotomy are poorly defined. We have hypothesized that CNS macrophages (microglia and hematogenous macrophages) exert divergent effects on tissue injury and repair after SCI as a result of microenvironmental factors that are specific to location (i.e., region within the spinal cord) and time post-injury. Studies in Aim 1 will use lasercapture microdissection in combination with microarray analysis to define gene expression patterns specific to resident and recruited CNS macrophages after SCI. It is likely these studies will reveal target genes that can be manipulated to modulate CNS macrophage function after SCI. Preliminary data suggest that activation of macrophages via Toll-like receptors (TLRs) can positively and negatively affect neuron/glial survival. Using rat and knockout mouse models of SCI, studies in Aim 2 will evaluate the anatomical and functional consequences of activating CNS macrophages via TLR2 or TLR4. In Aim 3, CX3CR1 and CD200 knock-out mice will be used to determine how removal of these endogenous macrophage regulatory proteins influences anatomical and functional recovery after SCI. The studies in this application should facilitate the development of molecular-based therapies designed to antagonize or promote macrophage-specific functions after SCI. For example, any significant functional and/or anatomical changes that are observed after SCI using knockout mice (Aims 2 or 3) can be traced back to a single gene product (e.g., fractalkine, CD200) that could be manipulated to improve functional recovery. Also, if specific genes are found to be regulated in macrophages after SCI (Aim 1), the promoter regions of those genes could be used to drive local and regulated production of growth factors or neurotrophins. In this way, CNS macrophages could be used as vehicles for drug delivery.

描述(申请人提供)：脊髓损伤(SCI)触发神经炎症反应，可加重组织损伤(例如，神经元死亡、轴突损伤、脱髓鞘)并促进修复(例如，轴突再生、髓鞘再生、血管重建)。这种功能二分法背后的细胞和分子机制还没有明确的定义。我们假设，中枢神经系统巨噬细胞(小胶质细胞和血源性巨噬细胞)在脊髓损伤后的组织损伤和修复中发挥不同的作用，这是由于损伤后特定位置(即脊髓内的区域)和时间的微环境因素的结果。AIM 1的研究将使用激光捕获显微切割结合微阵列分析来确定脊髓损伤后驻留和招募的CNS巨噬细胞特有的基因表达模式。这些研究很可能会揭示脊髓损伤后可被操纵来调节中枢神经系统巨噬细胞功能的靶基因。初步数据表明，通过Toll样受体(TLRs)激活巨噬细胞可以对神经元/神经胶质细胞的存活产生积极和消极的影响。使用大鼠和基因敲除小鼠的脊髓损伤模型，目标2的研究将评估通过TLR2或TLR4激活中枢神经系统巨噬细胞的解剖和功能后果。在AIM 3中，CX3CR1和CD200基因敲除小鼠将被用来确定去除这些内源性巨噬细胞调节蛋白对脊髓损伤后解剖和功能恢复的影响。这一应用的研究应该有助于开发基于分子的治疗方法，旨在拮抗或促进脊髓损伤后巨噬细胞的特异性功能。例如，使用基因敲除小鼠(目标2或3)在脊髓损伤后观察到的任何显著的功能和/或解剖变化都可以追溯到单一基因产物(例如，Fractalkine，CD200)，可以被操纵以改善功能恢复。此外，如果在脊髓损伤后发现巨噬细胞中有特定的基因被调控(目标1)，这些基因的启动子区域可以用来驱动局部和受调控的生长因子或神经营养因子的产生。通过这种方式，中枢神经系统巨噬细胞可以作为药物输送的载体。