Regulation of brain neuroprotection and inflammation by TIA1

TIA1 对脑神经保护和炎症的调节

基本信息

批准号：
9756292
负责人：
Benjamin L Wolozin
金额：
$ 24.75万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756292
关键词：
Affect Alzheimer&apos s Disease Antibodies Axon Axotomy Behavioral Biological Biology Brain Cells Cytoplasmic Granules Disease Disease Progression Excision Exhibits Exons Facial nerve structure Functional disorder Genes Genetic Crosses Glial Fibrillary Acidic Protein Glutamates Goals Hippocampus (Brain)Immune Immunohistochemistry Inflammation Inflammatory Inflammatory Response Kainic Acid Knock-out Knockout Mice Label Laboratories LacZ Genes Link Longevity LoxP-flanked allele Messenger RNA Microglia Modeling Mus Nerve Degeneration Neurons Organelles Pathway interactions Pattern Peripheral Phase Phenotype Process Proteins RNA RNA-Binding Proteins Regulation Reporter Role Site Stress Synapses Tauopathies Testing Work analog biological adaptation to stress calmodulin-dependent protein kinase II cell type cholinergic neuron experimental study frontal lobe hippocampal pyramidal neuron in vivo link protein mouse model neuroinflammation neuron loss neuronal cell body neuroprotection novel promoter response stem stress granule tau Proteins tau aggregation tau phosphorylation

项目摘要

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.

我们的实验室发现 RNA 结合蛋白 (RBP) 在病理生理学中的重要作用 tau蛋白病。 Tau 蛋白在神经元胞体中积累，作为正常生物途径的一部分，涉及平移应激反应和应激颗粒（SG）的形成。 tau 的关联 SG 还刺激 tau 聚集，表明 tau 聚集可以作为平移应激反应。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 TIA1 的水平（使 SGs 成核）显着延缓 P301S tau 小鼠的疾病进展。降低 RBP TIA1 减半 (TIA1+/-) 可使寿命延长 33%，并挽救突触损失、神经元损失、 6 个月时减少炎症和行为补救。这种强大的神经保护作用发生在 tau 寡聚化相应显着减少 (90%)。 TIA1 完整缺失分析透露出惊喜。 P301S TIA1-/- 小鼠寿命更长，并在 6 个月大时表现出行为拯救，然而，它们的反应性小胶质细胞也显着增加（>10倍），这表明它们具有强大的神经- 炎症反应。我们假设神经元中 TIA1 的去除会抑制神经变性，而从小胶质细胞中去除 TIA1 会增强神经炎症反应。两个替补这些情景可能可以解释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：TIA1 减少给神经元带来的好处更强比神经炎症增加造成的危害更大。情况 2：小胶质细胞中 TIA1 缺失产生一种令人惊讶地有益的神经炎症。该提案将产生有条件的在神经元或小胶质细胞中缺乏 TIA1 的 TIA1 敲除小鼠，并测试这些场景。目标 1：使用由胆碱能选择性启动子驱动的 CRE 生成条件 TIA1 敲除 (KO) 神经元 (ChAT)、额叶皮质和海马锥体神经元 (CamKII) 和小胶质细胞 (Cx3cr1)。通过免疫组织化学验证表达。目标 2：确定如何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小鼠来确定炎症反应是否增强使用面神经轴突切断术模型加剧炎症和神经退行性变。我们也会检查神经元选择性 TIA1 KO 小鼠以确定是否观察到针对轴切术模型以及谷氨酸类似物红藻氨酸的挑战。