Regulation of brain neuroprotection and inflammation by TIA1

我们实验室发现了RNA结合蛋白在病理生理学中的重要作用。 紧张症的症状。作为正常生物途径的一部分，tau在神经元胞体中积累，包括 平移应力响应和应力颗粒(SGS)的形成。牛磺酸与牛磺酸的联系 SGS还刺激tau聚集，表明tau聚集可以作为 翻译应激反应。我们最近的研究表明，RNA结合蛋白在 在活体内的紧张症。我们证明，降低RNA结合蛋白TIA1(这是 SGS)显著延缓了P301S tau小鼠的疾病进展。降低RBP TIA1减半(TIA1+/-)可延长33%的寿命，挽救突触丢失，神经元丢失， 在6个月时减少炎症和行为救援。这种强大的神经保护发生在 相应地，tau齐聚显著减少(90%)。TIA1基因全缺失分析 透露了一个惊喜。P301S TIA1-/-小鼠寿命更长，在6个月大时表现出行为救援， 然而，他们也表现出反应性小胶质细胞的显著增加(10倍)，这表明一个强大的神经细胞- 炎症反应。我们假设移除神经元中的TIA1可以抑制神经退行性变， 而从小胶质细胞中去除TIA1则增强了神经炎性反应。两个候补 情景可能解释了在面对增强的神经- 炎症反应。情景1：TIA1减少给神经元带来的好处更大 而不是神经炎症增加所造成的伤害。场景2：小胶质细胞中TIA1的缺失 产生一种神经炎症，这是令人惊讶的有益的。这项提议将产生有条件的 在神经元或小胶质细胞中缺乏TIA1的TIA1基因敲除小鼠，并测试这些情景。目标1： 用选择性胆碱能启动子驱动的Cre产生条件性TIA1基因敲除(KO) 神经元(ChAT)、额叶皮质和海马区锥体神经元(CaMKII)和小胶质细胞 (CX3CR1)。用免疫组织化学方法验证其表达。目标2：确定选择性删除 来自神经元或小胶质细胞的TIA1改变神经保护和炎症表型：我们将 使用小胶质细胞选择性TIA1 KO小鼠来确定增强的炎症反应 使用面神经切断模型，加剧炎症和神经变性。我们还将 检查神经元选择性TIA1 KO小鼠以确定是否观察到对 挑战轴突切断模型，以及谷氨酸类似物海人酸。

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.