MICROGLIAL ACTIVATION IN TRAUMATIC BRAIN INJURY

创伤性脑损伤中的小胶质细胞激活

• 批准号: 6193271
• 负责人: BEVERLY A RZIGALINSKI
• 金额: $ 29万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 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 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193271
• 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（大脑的免疫效应细胞）的激活。这 小胶质细胞在 TBI 中的作用是一把双刃剑，具有两面性： 神经保护和神经退行性作用。因此，治疗目标 将最大限度地减少负面的神经毒性小胶质细胞的作用，同时最大化 神经保护。剖析小胶质细胞与其他脑细胞的相互作用 小胶质细胞参与的生化途径的类型和鉴定 TBI 后的激活很难在体内完成。目前许多 体外小胶质细胞损伤模型不能再现其主要成分 TBI，即组织应变或拉伸。该提案的目标是 检查导致 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影响， 使用特征良好的体外拉伸损伤模型。我们最近的研究 证明小胶质细胞不会被拉伸损伤直接激活，但 被拉伸损伤的星形胶质细胞释放的可溶性因子激活。 激活的小胶质细胞形态发生改变，花生四烯酸增加 释放和增强细胞内钙信号传导一致 巨噬细胞激活。我们第一次发现了上调 激活小胶质细胞中谷氨酸介导的钙信号通路，这可能 在小胶质细胞和受伤的星形胶质细胞之间构成信号网络 神经元。我们还发现星形胶质细胞受到拉伸损伤并严重 受伤的神经元将 ATP 释放到细胞外空间。我们假设 创伤性损伤的星形胶质细胞和神经元释放的谷氨酸和 ATP 启动小胶质细胞趋化性激活。在本提案中，我们将 继续剖析涉及拉伸诱导的信号通路 通过检查谷氨酸介导的花生四烯酸释放来激活小胶质细胞 钙信号传导、形态变化、增殖、主要 组织相容性抗原表达、吞噬​​作用和趋化作用。我们将 还确定了拉伸激活的小胶质细胞改变的机制 神经元钙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、钙信号传导、嘌呤能和谷氨酸能 受体，我们将尝试抵消小胶质细胞的神经毒性。体外 剖析涉及神经保护和神经毒性的机制 创伤后的小胶质细胞可能会发展出更有效的 旨在通过改变 TBI 后继发性损伤的策略 小胶质细胞从神经毒性到神经保护作用的平衡。