MICROGLIAL ACTIVATION IN TRAUMATIC BRAIN INJURY

创伤性脑损伤中的小胶质细胞激活

• 批准号: 6892218
• 负责人: BEVERLY A RZIGALINSKI
• 金额: $ 30万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892218
• 关键词: arachidonate; biological signal transduction; brain injury; calcium flux; chemotaxis; disease /disorder model; glutamates; microglia; mixed tissue /cell culture; neuroimmunomodulation; neurotoxicology

DESCRIPTION (adapted from applicant's abstract): Traumatic brain injury (TBI) induces activation of microglia, the immune effector cells of the brain. The role of microglia in TBI is one of double-edged sword, having both neuroprotective and neurodegenerative effects. Therefore, a treatment goal would be to minimize negative, neurotoxic microglial actions while maximizing neuroprotection. Dissection of microglial interactions with other brain cell types and identification of biochemical pathways involved in microglial activation after TBI is difficult to accomplish in vivo. Many of the current models of in vitro microglial injury do not reproduce the major component of TBI, that being tissue strain or stretch. The goal of this proposal is to examine the signal transduction pathways responsible for TBI-induced microglial activation and determine the consequences of activation on neuronal injury, using a well-characterized in vitro stretch-injury model. Our recent studies demonstrate that microglia are not directly activated by stretch injury, but are activated by soluble factors released from stretch-injured astrocytes. Activated microglia had morphological alterations, increased arachidonic acid release, and enhanced intracellular calcium signaling consistent with macrophage activation. For the first time, we have identified upregulation of a glutamate-mediated calcium-signaling pathway in activated microglia, which may constitute a signaling network between microglia and injured astrocytes and neurons. We have also found that stretch-injured astrocytes and severely injured neurons release ATP into the extracellular space. We hypothesize that glutamate and ATP released by traumatically injured astrocytes and neurons initiates microglial chemotaxis activation. In the present proposal, we will continue to dissect the signaling pathways involved in stretch-induced microglial activation by examining arachidonic acid release, glutamate-mediated calcium signaling, morphological changes, proliferation, major histocompatibility antigen expression, phagocytosis, and chemotaxis. We will also determine the mechanisms through which stretch-activated microglia alter neuronal calcium signaling or exert neurotoxic effects. Using inhibitors of the arachidonic acid cascade, calcium signaling, purinergic and glutamatergic receptors, we will attempt to counteract microglial neurotoxicity. In vitro dissection of the mechanisms involved in the neuroprotection and neurotoxicity of microglia after trauma could permit the development of more effective strategies aimed at reduction of secondary injury after TBI by shifting the balance of microglial effects from neurotoxic to neuroprotective.

描述（改编自申请人的摘要）：创伤性脑损伤（TBI） 诱导小胶质细胞激活，即大脑的免疫效应细胞。这 小胶质细胞在TBI中的作用是双刃剑之一，两者都具有 神经保护作用和神经退行性作用。因此，一个治疗目标 将最大程度地减少神经毒性小胶质细胞作用，同时最大化 神经保护。与其他脑细胞的小胶质相互作用解剖 小胶质细胞的生化途径的类型和鉴定 TBI后的激活很难在体内完成。许多电流 体外小胶质细胞损伤的模型不会重现 TBI，是组织应变或拉伸。该提议的目的是 检查负责TBI诱导的小胶质细胞的信号转导途径 激活并确定激活对神经元损伤的后果， 使用良好的体外拉伸伤害模型。我们最近的研究 证明小胶质细胞不是被拉伸损伤直接激活，而是 被伸展伤害的星形胶质细胞释放的可溶因子激活。 活化的小胶质细胞具有形态学改变，蛛网膜酸增加 释放和增强的细胞内钙信号传导与 巨噬细胞激活。我们第一次确定了 活化小胶质细胞中的谷氨酸介导的钙信号途径，这可能 构成小胶质细胞和受伤的星形胶质细胞之间的信号网络， 神经元。我们还发现伸展的星形胶质细胞严重 受伤的神经元ATP释放到细胞外空间。我们假设这一点 谷氨酸和ATP由创伤受伤的星形胶质细胞和神经元释放 引发小胶质细胞趋化激活。在本提案中，我们将 继续剖析与拉伸引起的有关的信号通路 小胶质细胞激活通过检查谷氨酸释放，谷氨酸介导的 钙信号传导，形态变化，增殖，主要 组织相容性抗原表达，吞噬作用和趋化性。我们将 还确定拉伸激活的小胶质细胞改变的机制 神经元信号传导或发挥神经毒性作用。使用抑制剂 花生四烯酸级联，钙信号，嘌呤能和谷氨酸能 受体，我们将尝试抵消小胶质细胞神经毒性。体外 对神经保护和神经毒性涉及的机制的解剖 创伤后的小胶质细胞可以允许发展更有效 旨在减少TBI后继发伤害的策略 从神经毒性到神经保护作用的小胶质效应平衡。