Intranasal tat alters gene expression in the mouse brain.
Intranasal tat alters gene expression in the mouse brain.
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鼻内tat改变小鼠大脑中的基因表达。
DOI：
10.1007/s11481-006-9053-z
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发表时间：
2007
期刊：
影响因子：
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通讯作者：
Hanson,LeahR
中科院分区：
文献类型：
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作者：
Pulliam,Lynn;Sun,Bing;Rempel,Hans;Martinez,PaulaM;Hoekman,JohnD;Rao,ReshmaJ;Frey2nd,WilliamH;Hanson,LeahR
研究人员对衰老小鼠鼻内 (IN) 递送 HIV-1 Tat 作为大脑中 HIV-1 感染的可能模型进行了研究。 IN施用后，通过放射自显影和伽玛计数评估瑞士韦伯斯特小鼠大脑中[125I]标记的Tat的分布。 [125I] 标记的 Tat 在嗅球、颈淋巴结和三叉神经束中检测到浓度最高。在另一项实验中，APPSw 转基因小鼠被用来模拟慢性 Tat 暴露。小鼠每周用 6 μg Tat (n= 4) 或媒介物 (n= 4) 鼻内治疗 3 次，持续 4 周。从额叶皮层分离总RNA，并使用基因微阵列进行差异基因表达分析。基因本体图谱表明先天免疫、炎症和细胞凋亡反应。 RT-PCR 验证了经 Tat 治疗的小鼠中五个感兴趣的基因在微阵列中显着升高。 Toll 样受体 9 (Tlr9) 是一种基因，此前已被证明可以激活信号级联，从而产生先天免疫并增强 HIV-1 基因表达。第二个基因 Fas 在神经炎症中起着关键作用。两种与趋化性相关的富含半胱氨酸的细胞因子升高：MCP-1 (Ccl2)（对单核细胞趋化）和 Ccl17 (TARC)（对淋巴细胞趋化）。最后，基因sestrin显着升高，并且与氧化应激有关，特别是β淀粉样蛋白诱导的氧化应激。这种神经炎症 IN Tat 模型可能有助于研究 HIV-1 诱导的神经变性。
Intranasal (IN) delivery of HIV-1 Tat in aging mice was investigated as a possible model for HIV-1 infection in the brain. After IN administration, the distribution of [125I]-labeled Tat in the brains of Swiss Webster mice was evaluated by autoradiography and gamma counting. [125I]-labeled Tat was detected at the highest concentrations in the olfactory bulb, cervical nodes, and trigeminal nerve tract. In another experiment, APPSw transgenic mice were used to model chronic Tat exposure. The mice were treated intranasally with 6 μg Tat (n= 4) or vehicle (n= 4) three times per week for 4 weeks. Total RNA was isolated from the frontal cortex, and differential gene expression analysis was performed using gene microarrays. Gene ontology profiles indicated innate immunity, inflammatory and apoptotic responses. Five genes of interest in the Tat-treated mice that were significantly elevated in the microarrays were validated by RT-PCR. One gene, the Toll-like receptor 9 (Tlr9), has previously been shown to activate signaling cascades leading to innate immunity and enhanced HIV-1 gene expression. A second gene, Fas, plays a key role in neuroinflammation. Two cysteine-rich cytokines associated with chemotaxis were elevated: MCP-1 (Ccl2), which is chemotactic for monocytes, and Ccl17 (TARC), which is chemotactic for lymphocytes. Finally, the gene sestrin was significantly elevated and has been associated with oxidative stress, in particular amyloid beta-induced oxidative stress. This IN Tat model of neuroinflammation may be useful to study HIV-1-induced neurodegeneration.