MACROPHAGE HETEROGENEITY AFTER SPINAL CORD INJURY

脊髓损伤后的巨噬细胞异质性

• 批准号: 6187384
• 负责人: PHILLIP G POPOVICH
• 金额: $ 21.41万
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187384
• 关键词: angiogenesis; bone marrow transplantation; cell transplantation; cytokine; digital imaging; enzyme linked immunosorbent assay; experimental brain lesion; flow cytometry; free radical scavengers; genetic techniques; immunocytochemistry; inflammation; laboratory rat; leukocyte activation /transformation; macrophage; microglia; myelinopathy; necrosis; nervous system regeneration; neural degeneration; neurotrophic factors; phagocytosis; sectioning; spinal cord injury

This research will investigate to what extent the reparative potential of macrophages exists within the traumatically injured spinal cord. Historically, macrophages have been considered inflammatory scavenger cells in the CNS, capable only of removing cellular debris at sites of injury or infection. Now, many functions have been attributed to these cells including the ability to promote blood vessel growth, myelination, and neurite sprouting/regeneration. Unfortunately, these same cells can promote demyelination and cell injury. How and under what conditions macrophages effect such a broad range of biological functions is not clear, but may result from changes in the lesion microenvironment. It is the major hypothesis of this proposal that the inherent ability of macrophages to promote tissue repair and functional recovery changes as a function of time after spinal cord injury (SCI) and is negatively influenced by the accumulation of blood-borne elements (cells and proteins) at the injury site. Using radiation bone marrow chimeric rats in combination with macrophage and complement-depletion protocols, we will examine how these vascular constituents influence resident (microglia) and recruited (blood-derived) macrophage activation and function. Specifically, the neurotrophic and oxidative capacity of each macrophage subpopulation will be evaluated in vivo using immunohistochemistry and in vitro using cytokines and other factors present in the injury site to trigger macrophage effector functions. Cells exhibiting neurotrophic secretory profiles will be transplanted into injured rat spinal cords to test their ability to promote regeneration and functional recovery. By learning more about the factors that influence macrophage function in the injured CNS, we may be able to harness the innate reparative potential of the inflammatory response (specifically macrophages) to promote functional regeneration. Moreover, we will be determining the feasibility of manipulating an intrinsic component of the injury site to promote tissue repair. Such an approach may be biologically and clinically advantageous and could eliminate the need for chronic drug therapy.

本研究将探讨巨噬细胞在多大程度上存在创伤性脊髓损伤的修复潜力。历史上，巨噬细胞被认为是中枢神经系统中的炎症清除细胞，只能清除损伤或感染部位的细胞碎片。现在，许多功能都归功于这些细胞，包括促进血管生长、髓鞘形成和神经突发芽/再生的能力。不幸的是，这些细胞可以促进脱髓鞘和细胞损伤。巨噬细胞如何以及在什么条件下发挥如此广泛的生物学功能尚不清楚，但可能是病变微环境改变的结果。该提议的主要假设是，巨噬细胞促进组织修复和功能恢复的固有能力在脊髓损伤（SCI）后随着时间的推移而改变，并受到损伤部位血源性元素（细胞和蛋白质）积累的负面影响。使用放射骨髓嵌合大鼠结合巨噬细胞和补体耗竭方案，我们将研究这些血管成分如何影响常驻（小胶质细胞）和招募（血源性）巨噬细胞的激活和功能。具体来说，将在体内使用免疫组织化学评估每个巨噬细胞亚群的神经营养和氧化能力，在体外使用存在于损伤部位的细胞因子和其他因子来触发巨噬细胞效应功能。具有神经营养分泌特征的细胞将被移植到受伤的大鼠脊髓中，以测试它们促进再生和功能恢复的能力。通过了解更多影响受损中枢神经系统巨噬细胞功能的因素，我们可能能够利用炎症反应（特别是巨噬细胞）的先天修复潜力来促进功能再生。此外，我们将确定操纵损伤部位的内在成分以促进组织修复的可行性。这种方法可能在生物学和临床上都是有利的，并且可以消除对慢性药物治疗的需要。