ROLE OF CALCINEURIN IN ASTROCYTE ACTIVATION ASSOCIATED WITH ALZHEIMER?S DISEASE

钙调磷酸酶在与阿尔茨海默病相关的星形胶质细胞激活中的作用

• 批准号: 7382167
• 负责人: Christopher Mark Norris
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382167
• 关键词: ROLE; CALCINEURIN; ASTROCYTE; ACTIVATION; ASSOCIATED

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer?s Disease (AD) and other neurodegenerative syndromes are accompanied by a pronounced immune/inflammatory response (e.g. activated neuroglia and elevated cytokine levels) that could contribute significantly to widespread neuronal death and deterioration. In lymphocytes and other cell types, the Ca2+/calmodulin dependent protein phosphatase, calcineurin, along with its target transcription factor NFAT (nuclear factor of activated T cells) have long been recognized to induce numerous immune/inflammatory signaling cascades. As such, it is somewhat surprising that the calcineurin/NFAT pathway has not been investigated extensively for a similar role in neuro-immune/inflammatory signaling. Recently, we showed that calcineurin immunostaining is markedly upregulated in activated astrocytes in hippocampus and neocortex of transgenic AD model mice (Norris et al., J Neurosci 25:4649, 2005). Moreover, overexpression of activated calcineurin in mixed (neuronal and glial) hippocampal cultures induced ?activation-like? changes in astrocytes (i.e. pronounced hypertrophy of soma and processes) and also triggered the expression of most genetic markers for the activated phenotype, including numerous immune/inflammatory factors. The results suggest that, similar to its well-known role in lymphocytes, calcineurin also may serve as a critical upstream regulator of immune/inflammatory signaling cascades associated with astrocyte activation and AD. Using astrocyte-enriched cell cultures and viral-mediated gene transfer, the proposed research will extend our earlier work by determining whether endogenous inflammatory mediators recruit the calcineurin/NFAT pathway in astrocytes en route to the expression of a panel of molecular markers for the activated astrocyte phenotype. Furthermore, adeno-associated viruses encoding an astrocyte-specific promoter will be used to determine if calcineurin/NFAT activity in astrocytes contributes significantly to the neuropathological changes and cognitive deficits found in amyloid-bearing AD model mice.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。阿尔茨海默病 (AD) 和其他神经退行性综合征伴有明显的免疫/炎症反应（例如神经胶质细胞激活和细胞因子水平升高），这可能会导致广泛的神经元死亡和恶化。在淋巴细胞和其他细胞类型中，Ca2+/钙调蛋白依赖性蛋白磷酸酶、钙调神经磷酸酶及其靶转录因子 NFAT（活化 T 细胞的核因子）长期以来被认为可诱导大量免疫/炎症信号级联反应。因此，令人惊讶的是，钙调神经磷酸酶/NFAT 通路在神经免疫/炎症信号传导中的类似作用尚未得到广泛研究。最近，我们发现转基因 AD 模型小鼠海马和新皮质中激活的星形胶质细胞中的钙调神经磷酸酶免疫染色显着上调（Norris 等人，J Neurosci 25：4649，2005）。此外，在混合（神经元和神经胶质）海马培养物中激活的钙调神经磷酸酶的过度表达诱导了“类似激活”？星形胶质细胞的变化（即胞体和突起明显肥大），并且还触发了激活表型的大多数遗传标记的表达，包括许多免疫/炎症因子。结果表明，与众所周知的在淋巴细胞中的作用类似，钙调神经磷酸酶也可能作为与星形胶质细胞激活和 AD 相关的免疫/炎症信号级联的关键上游调节剂。 使用富含星形胶质细胞的细胞培养物和病毒介导的基因转移，拟议的研究将通过确定内源性炎症介质是否在星形胶质细胞中招募钙调神经磷酸酶/NFAT途径来表达活化星形胶质细胞的一组分子标记物，从而扩展我们早期的工作表型。此外，编码星形胶质细胞特异性启动子的腺相关病毒将用于确定星形胶质细胞中的钙调神经磷酸酶/NFAT活性是否对淀粉样蛋白AD模型小鼠中发现的神经病理变化和认知缺陷有显着贡献。