Transcriptomic and Proteomic Analysis of Tau-dependent E/I Imbalance

Tau 依赖性 E/I 失衡的转录组学和蛋白质组学分析

• 批准号: 10789541
• 负责人: Lennart Mucke
• 金额: $ 51.98万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-16 至 2025-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10789541
• 关键词: Ablation; Affect; Alzheimer' s Disease; Amyloid Proteins; Animal Model; Binding; Brain; Brain Diseases; Chemicals; Coupled; Data; Data Set; Development; Disease; Disease model; Drug Targeting; Epilepsy; Evaluation; Experimental Designs; Genes; Health; Injections; Kainic Acid; Label; Light; Liquid Chromatography; Mediator; Messenger RNA; Metabolic; Molecular; Molecular Profiling; Mouse Protein; Mus; Mutation; Neurons; Neurotransmitter Receptor; Pathologic; Pathway interactions; Post-Translational Protein Processing; Potassium Channel; Process; Prosencephalon; Proteins; Proteomics; Refractory; Signal Pathway; Sodium Channel; Stroke; Testing; Therapeutic; Transcript; Western Blotting; autism spectrum disorder; brain cell; cell type; cohort; comparative; excitatory neuron; gene product; insight; mouse model; neural; neural network; new therapeutic target; novel; pharmacologic; prevent; single nucleus RNA-sequencing; tandem mass spectrometry; targeted treatment; tau Proteins; tau interaction; transcriptomics

SUMMARY Evidence for excitation/inhibition (E/I) imbalance of neural networks has been found in diverse brain disorders that are prevalent, devastating, and refractory or poorly responsive to available therapies, including Alzheimer’s disease (AD), epilepsy, and autism spectrum disorders. In animal models for these conditions, reducing overall levels of non-aggregated, endogenous, wildtype tau prevents or diminishes disease manifestations triggered by diverse causes, ranging from the neural accumulation of amyloid proteins to mutations in genes encoding sodium or potassium channels, stroke, and the pharmacological blockade of neurotransmitter receptors. Since all of these abnormalities promote E/I imbalance and network hyperexcitability, which can disrupt important processes required for the health of neurons and other brain cells, we hypothesize that the reduced E/I ratio in tau-deficient brains explains, at least in good part, the broad therapeutic benefits of overall tau reduction. Here, we propose to explore the underlying molecular mechanisms by combining cell type-specific tau ablation and chemically induced E/I imbalance with molecular profiling analyses focused on excitatory forebrain neurons. Previous studies have revealed that tau can bind to or interact with a plethora of other proteins. Because many, if not most, of these tau-interacting proteins have the potential to affect neuronal activities, the primary mechanisms by which tau enables and tau reduction counteracts network hyperexcitability remain to be determined. In light of our recent discovery that selective ablation of tau in excitatory, but not inhibitory, neurons is sufficient to counteract E/I imbalance, we hypothesize that these mechanisms can be revealed by comparing the molecular profile of excitatory neurons that do or do not express tau before and during the emergence of chemically induced network hyperexcitability. We propose to test this hypothesis at the mRNA level (Aim 1) and at the protein level (Aim 2). Because of complementary strengths and weaknesses of these approaches and our related experimental designs, we further hypothesize that an integrative analysis of the resulting datasets (Aim 3) has the best chance to pinpoint the most critical mechanisms by which tau enables and tau reduction counteracts the development of E/I imbalance under pathological conditions. Identifying these mechanisms could provide new insights into the pathobiology of tau, help guide the development and evaluation of tau-targeting therapeutics, and result in the identification of additional indications and drug targets.

总结 神经网络兴奋/抑制（E/I）失衡的证据已在多种脑疾病中发现 这些疾病普遍存在，具有破坏性，难治性或对现有疗法反应不良，包括阿尔茨海默氏症 疾病（AD）、癫痫和自闭症谱系障碍。在这些疾病的动物模型中， 非聚集的内源性野生型tau的水平预防或减少由以下因素引发的疾病表现： 多种原因，从淀粉样蛋白的神经积累到编码钠的基因突变， 或钾通道、中风和神经递质受体的药理学阻断。由于所有 这些异常促进E/I失衡和网络过度兴奋，这可能会破坏重要的过程 神经元和其他脑细胞的健康所需的，我们假设，在tau蛋白缺乏的E/I比降低， Brains至少在很大程度上解释了总体tau蛋白减少的广泛治疗益处。在这里，我们建议 通过结合细胞类型特异性tau蛋白消融和化学方法来探索潜在的分子机制， 诱导的E/I不平衡，分子谱分析集中于兴奋性前脑神经元。先前 研究表明，tau蛋白可以与大量其他蛋白质结合或相互作用。因为很多人，如果不是 这些tau蛋白相互作用的蛋白质中的大多数具有影响神经元活动的潜力， τ通过何种方式启用和τ减少抵消网络超兴奋性仍有待确定。鉴于 我们最近发现，选择性消融兴奋性神经元中的tau蛋白，而不是抑制性神经元， 抵消E/I失衡，我们假设这些机制可以通过比较分子水平来揭示。 在化学诱导的神经元出现之前和期间表达或不表达tau的兴奋性神经元的概况 网络过度兴奋我们建议在mRNA水平（目标1）和蛋白质水平上检验这一假设 (Aim 2）的情况。由于这些方法和我们的相关方法的互补优势和弱点， 实验设计，我们进一步假设，综合分析所得数据集（目标3） 最好的机会，以查明最关键的机制，其中tau使和tau减少抵消 病理条件下E/I失衡的发展。确定这些机制可以提供 对tau蛋白病理生物学的新见解，有助于指导tau蛋白靶向的开发和评估 治疗，并导致额外的适应症和药物靶点的鉴定。