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结合蛋白网络在直立性痴呆和相关痴呆中的作用 痴呆症，包括阿尔茨海默病(AD)、额颞叶变性(FTLD)和 在我们日益老龄化的社会中，相关疾病成为一个主要的挑战。.的存在 含有tau蛋白的神经原纤维缠结是AD和AD的主要神经病理特征 相关痴呆症。尽管RNA结合蛋白(RBPs)正在成为这些 神经退行性疾病，对控制平衡的RBP网络知之甚少 人类tau基因或其他痴呆相关基因(DAGs)的表达。基于 已发表的研究和初步数据，我们建议检验RBP-tau的假设 维持tau选择性剪接和tau mRNA表达平衡的调控网络包括 在tauopathy中被破坏，导致tau拼接异常并导致病理性tau 聚集和神经变性。我们计划利用大量的rna-seq和蛋白质组学数据。 构建RBP-tau基因调控网络，并利用新开发的人Tau基因敲除- 在(HTauKI)小鼠模型中与患者样本和IPSC神经元一起验证关键因素 导致痴呆症和相关的神经官能症的发病机制。我们将确定RBP 通过检测候选AD相关限制性商业惯例对痴呆患者的基因和网络的影响 结合生物信息学和分子方法对患者样本进行独立队列研究 (目标1)。我们将使用hTauKI小鼠和IPSC-1来表征RBP-tau RNA相互作用组。 衍生神经元(目标2)。我们将确定RBP-tau调控网络在tau中的作用。 候选限制性商业惯例调节tau前-mRNA分子机制的神经毒性研究 剪接和tau发病机制(目标3)。我们的综合多学科方法结合了 用全新的hTauKI小鼠进行最先进的分子/生化分析的生物信息学 模型和IPSC来源的人类神经元。这将使我们能够构建RBP-tau调控 对正常大脑功能和tau发病机制至关重要的网络。拟议的研究将不会 只会促进我们对复杂的转录后调控表达机制的理解 并提供对RBP-tau网络功能的机械性见解，但也导致 有助于开发新的痴呆症诊断和治疗工具的信息。