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: 7610714
• 负责人: Christopher Mark Norris
• 金额: $ 2.92万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610714
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Astrocytes; Biological Markers; Biological Response Modifiers; Calcineurin; Calmodulin; Cessation of life; Cognitive deficits; Computer Retrieval of Information on Scientific Projects Database; Cultured Cells; Dependovirus; Deterioration; Funding; Gene Transfer; Genetic Markers; Grant; Hippocampus (Brain); Hypertrophy; Immune; Inflammatory; Inflammatory Response; Institution; Lymphocyte; Mediating; Mediator of activation protein; Mus; NF-AT; Neocortex; Nerve Degeneration; Neuroglia; Neurons; Pathway interactions; Phenotype; Process; Protein Overexpression; Protein phosphatase; Recruitment Activity; Research; Research Personnel; Resources; Role; Route; Signal Transduction; Source; Syndrome; United States National Institutes of Health; Viral; Work; cell type; cytokine; neuronal cell body; nuclear factors of activated T-cells; promoter; transcription factor; transgenic model of alzheimer disease

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 阿尔茨海默氏病（AD）和其他神经退行性综合症伴随着明显的免疫/炎症反应（例如，活化的神经胶质和细胞因子水平升高），可能会对广泛的神经元死亡和恶化产生重大贡献。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，钙调神经蛋白及其靶向转录因子NFAT（活化T细胞的核因子）长期以来已被识别为诱导许多免疫/炎症信号囊泡。 因此，令人惊讶的是，在神经免疫/炎症信号传导中，没有对钙调神经磷酸酶/NFAT途径进行广泛研究。最近，我们表明钙调神经蛋白免疫染色在激活的星形胶质细胞和转基因AD模型小鼠的新皮层中明显上调（Norris等，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蛋白的过表达诱导了激活样？星形胶质细胞的变化（即明显的SOMA和过程肥大），还触发了激活表型的大多数遗传标志物的表达，包括许多免疫/炎症因子。结果表明，与其在淋巴细胞中的众所周知作用相似，钙调神经酶也可以作为与星形胶质细胞激活和AD相关的免疫/炎症信号传导级联反应的关键上游调节剂。 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，提出的研究将通过确定内源性炎症介体是否募集了星形胶质层中的钙调神经素/NFAT途径，以扩展我们的早期工作，并在星形胶质细胞中募集钙调蛋白/NFAT途径，以表达分子标记的表达，用于激活的星形镜现象。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活性是否对在淀粉样淀粉样蛋白承重的AD模型小鼠中发现的神经病理学变化和认知障碍产生显着贡献。