Regulation of brain neuroprotection and inflammation by TIA1

我们的实验室发现了RNA结合蛋白（RBP）在病理生理学中的重要作用 tau蛋白病Tau在神经元索马体中积累，作为正常生物学途径的一部分， 平移应力反应和应力颗粒（SGs）的形成。tau蛋白与 SGs还刺激tau聚集，表明tau聚集可以正常发生，作为tau聚集的一部分。 翻译应激反应我们最近的研究表明，RNA结合蛋白在 体内tau蛋白病。我们证明，降低RNA结合蛋白TIA 1（ 成核SG）显著延迟P301 S tau小鼠中的疾病进展。降低RBP TIA 1减半（TIA 1 +/-）使寿命延长33%，并挽救了突触丢失，神经元丢失， 在6个月时减少炎症和行为拯救。这种强大的神经保护作用发生在 tau寡聚化的相应显著（90%）减少。完整TIA 1缺失的分析 露出了惊喜的表情。P301 S TIA 1-/-小鼠寿命更长，并在6个月时表现出行为拯救， 然而，它们也表现出反应性小胶质细胞的显著增加（>10倍），表明它们具有强烈的神经- 炎症反应。我们假设神经元中的TIA 1去除抑制了神经变性， 而从小胶质细胞中去除TIA 1增强了神经炎症反应。两名候补 这种情况可能解释了在面对增强的神经保护时神经保护的存在， 炎症反应。场景1：TIA 1减少对神经元的益处更强 而不是增加神经炎症所造成的伤害。场景2：小胶质细胞中TIA 1的丢失 产生一种神经炎症，这是非常有益的。该提案将产生有条件的 TIA 1基因敲除的小鼠在神经元或小胶质细胞中缺乏TIA 1，并测试这些情况。目标1： 用胆碱能选择性启动子驱动的CRE产生条件性TIA 1敲除（KO） 神经元（ChAT）、额叶皮质和海马的锥体神经元（CamKII）和小胶质细胞 （Cx3cr1）。通过免疫组织化学验证表达。目标2：确定选择性删除 来自神经元或小胶质细胞的TIA 1改变神经保护和炎症表型：我们将 使用小胶质细胞选择性TIA 1 KO小鼠来确定增强的炎症反应是否 加剧炎症和神经变性。我们还将 检查神经元选择性TIA 1 KO小鼠，以确定是否观察到针对 挑战与轴突切断模型，以及谷氨酸类似物，红藻氨酸。

Our laboratory discovered an important role for RNA binding proteins (RBPs) in the pathophysiology of tauopathy. Tau accumulates in the neuronal soma as part of a normal biological pathway involving the translational stress response, and formation of stress granules (SGs). The association of tau with SGs also stimulates tau aggregation, indicating that tau aggregation can occur normally as part of the translational stress response. Our recent studies demonstrate a key role for RNA binding proteins in tauopathy in vivo. We demonstrated that reducing levels of the RNA binding protein TIA1 (which nucleates SGs) significantly delays disease progression in the P301S tau mouse. Reducing the RBP TIA1 by half (TIA1+/-) yielded a 33% increase in lifespan, with rescue of synaptic loss, neuronal loss, reduced inflammation and behavioral rescue at 6 months. This strong neuroprotection occurs with a corresponding dramatic (90%) reduction in tau oligomerization. Analysis of the full TIA1 deletion revealed a surprise. The P301S TIA1-/- mice live longer and show behavioral rescue at 6-months, however, they also exhibit a major (>10-fold) increase in reactive microglia, suggesting a strong neuro- inflammatory response. We hypothesize that TIA1 removal in neurons inhibits neurodegeneration, while TIA1 removal from microglia enhances the neuro-inflammatory response. Two alternate scenarios might explain the presence of neuroprotection in the face of an enhanced neuro- inflammatory response. Scenario 1: The benefit accrued to neurons from TIA1 reduction is stronger than the harm resulting from the increased neuro-inflammation. Scenario 2: Loss of TIA1 in microglia produces a neuro-inflammation that is surprisingly beneficial. This proposal will produce conditional TIA1 knockout mice that lack TIA1 in either neurons or microglia, and test these scenarios. Aim 1: Generate conditional TIA1 knockouts (KO) with CRE driven by promoters selective for cholinergic neurons (ChAT), pyramidal neurons of the frontal cortex and hippocampus (CamKII), and microglia (Cx3cr1). Validate expression by immunohistochemistry. Aim 2: Determine how selective deletion of TIA1 from neurons or microglia modifies the neuroprotective and inflammatory phenotypes: We will use the microglial selective TIA1 KO mice to determine whether the enhanced inflammatory response exacerbates inflammation and neurodegeneration, using the facial nerve axotomy model. We will also examine the neuronal selective TIA1 KO mice to determine if protection is observed against a challenge with the axotomy model, as well as the glutamate analogue, kainic acid.