The Role of RNA Binding Protein Networks in Tauopathy and Related Dementia

RNA 结合蛋白网络在 Tau 病和相关痴呆中的作用

• 批准号: 10034785
• 负责人: ROBERT J VASSAR
• 金额: $ 309.02万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10034785
• 关键词: Affect; Aging; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Biochemical; Bioinformatics; Biological Assay; Brain; Brain region; Cell Line; Complex; Custom; Data; Data Set; Degenerative Disorder; Dementia; Disease; Elements; Exons; Frontotemporal Lobar Degenerations; Future; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic Transcription; Genetic study; Goals; Human; Impaired cognition; Individual; Introns; Knock-in; Knock-in Mouse; Lead; Messenger RNA; Methods; Modeling; Molecular; Multiomic Data; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Play; Protein Isoforms; Proteomics; Public Health; Publishing; RNA; RNA Splicing; RNA analysis; RNA-Binding Proteins; Regulation; Regulator Genes; Role; Sampling; Societies; Spliceosomes; Tauopathies; Testing; Work; base; cognitive function; cohort; design; gene product; genetic regulatory protein; in vivo; indexing; induced pluripotent stem cell; innovation; insight; interdisciplinary approach; mRNA Expression; mRNA Precursor; mouse model; neurotoxicity; novel diagnostics; novel therapeutics; protein expression; resilience; risk variant; tau Proteins; tau aggregation; tau expression; therapeutic development; tool; transcriptome sequencing; treatment strategy

The Role of RNA Binding Protein Networks in Tauopathy and Related Dementia Dementias, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD) and related diseases, become a leading challenge in our progressively aging society. The presence of tau protein-containing neurofibrillary tangles is a major neuropathological hallmark of AD and related dementia. Although RNA binding proteins (RBPs) are emerging as critical players in these neurodegenerative diseases, little is known about the RBP networks that control the balanced expression of the human tau gene or other dementia-associated genes (DAGs). Based on published studies and preliminary data, we propose to test the hypotheses that the RBP-tau regulatory networks that maintain balanced tau alternative splicing and tau mRNA expression are disrupted in tauopathies, leading to aberrant tau splicing and contributing to pathological tau aggregation and neurodegeneration. We plan to leverage the vast RNA-seq and proteomics data to construct RBP-tau gene regulatory networks and to use the newly developed human Tau knock- in (hTauKI) mouse model together with patient samples and iPSC neurons to validate key players contributing to the pathogenesis of dementia and related tauopathies. We will determine RBP genes and networks affected in dementia by examining candidate AD-associated RBPs in independent cohorts of patient samples using combined bioinformatics and molecular approaches (Aim 1). We will characterize RBP-tau RNA interactome using the hTauKI mice and using iPSC- derived neurons (Aim 2). We will determine the role of RBP-tau regulatory networks in tau neurotoxicity by dissecting molecular mechanisms of candidate RBPs in regulating tau pre-mRNA splicing and in tau pathogenesis (Aim 3). Our integrated multi-disciplinary approach combines bioinformatics with state-of-art molecular/biochemical assays with the brand-new hTauKI mouse model and iPSC-derived human neurons. This will enable us to construct RBP-tau regulatory networks critical for normal brain function and for tau pathogenesis. The proposed study will not only advance our understanding of complex post-transcriptional mechanisms regulating expression of DAGs and provide mechanistic insights into the function of RBP-tau networks, but also lead to information useful for developing new diagnostic and therapeutic tools for dementia.

RNA结合蛋白网络在Tau病及相关痴呆中的作用 痴呆，包括阿尔茨海默病（AD）、额颞叶变性（FTLD）和阿尔茨海默病（AD）。 在我们这个日益老龄化的社会中，与疾病相关的疾病成为一个主要挑战。的存在 含tau蛋白的神经元缠结是AD的主要神经病理学标志， 痴呆症相关尽管RNA结合蛋白（RBP）正在成为这些领域的关键参与者， 神经退行性疾病，很少有人知道RBP网络控制的平衡 人tau基因或其它痴呆相关基因（DAG）的表达。基于 根据已发表的研究和初步数据，我们建议测试RBP-tau蛋白 维持平衡的tau可变剪接和tau mRNA表达的调控网络， 在tau蛋白病中被破坏，导致异常的tau剪接并促成病理性tau蛋白 聚集和神经变性。我们计划利用大量的RNA测序和蛋白质组学数据 构建RBP-tau基因调控网络，并使用新开发的人Tau敲除- 在（hTauKI）小鼠模型中与患者样品和iPSC神经元一起验证关键参与者 导致痴呆和相关的tau蛋白病的发病机制。我们将确定RBP 通过检查候选AD相关RBP， 使用组合的生物信息学和分子方法的患者样本的独立群组 (Aim 1）。我们将使用hTauKI小鼠和使用iPSC表征RBP-tau RNA相互作用组。 衍生神经元（Aim 2）。我们将确定RBP-tau调控网络在tau蛋白中的作用， 通过剖析候选RBP在调节tau前mRNA中的分子机制的神经毒性 剪接和tau发病机制（Aim 3）。我们的综合多学科方法结合了 使用全新hTauKI小鼠进行最先进的分子/生物化学测定的生物信息学 模型和iPSC衍生的人类神经元。这将使我们能够构建RBP-tau调控 网络对于正常脑功能和tau发病机制至关重要。拟议的研究将不 这只会促进我们对复杂的转录后机制的理解， 的DAG，并提供对RBP-tau网络功能的机械见解，但也导致 这些信息有助于开发痴呆症的新诊断和治疗工具。