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.

我们的实验室发现了RNA结合蛋白（RBP）在病理生理学中的重要作用 tauopathy。 tau作为正常生物途径的一部分在神经元中积聚压力颗粒（SGS）的翻译应力反应和形成。 tau与 SG还刺激了Tau聚集，表明Tau聚集正常发生作为翻译应力反应。我们最近的研究表明RNA结合蛋白在 tauopathy in Vivo。我们证明了降低RNA结合蛋白TIA1的水平（ SGS）显着延迟了P301S Tau小鼠的疾病进展。减少RBP TIA1乘一半（TIA1 +/-）产生了33％的寿命，并挽救了突触损失，神经元损失，减少了6个月的炎症和行为救援。这种强大的神经保护是在 tau低聚的相应戏剧性（90％）降低。整个TIA1删除的分析揭示了一个惊喜。 P301S TIA1 - / - 小鼠的寿命更长，在6个月的行为救援时期，然而，它们还表现出反应性小胶质细胞的大幅增加（> 10倍），表明有强的神经胶质细胞炎症反应。我们假设神经元中的TIA1去除会抑制神经变性，而从小胶质细胞中除去TIA1会增强神经炎症反应。两个替代面对增强的神经作用，情景可能解释了神经保护的存在炎症反应。方案1：降低TIA1的神经元的益处更强而不是因神经炎症增加而造成的伤害。方案2：小胶质细胞中TIA1的丢失产生一种令人惊讶的有益的神经炎症。该建议将产生有条件的 TIA1敲除小鼠在神经元或小胶质细胞中缺乏TIA1，并测试这些情况。目标1：由促进者选择胆碱能驱动的CRE产生有条件的TIA1敲除（KO）神经元（CHAT），额叶皮质和海马（CAMKII）和小胶质细胞的锥体神经元（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修饰神经保护和炎症表型：我们将使用小胶质选择性TIA1 KO小鼠来确定增强的炎症反应是否增强使用面神经轴切开术模型加剧了炎症和神经变性。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A 轴突切开术模型以及谷氨酸类似物的挑战。