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
基本信息
- 批准号:10034785
- 负责人:
- 金额:$ 309.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAgingAlternative SplicingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease related dementiaAmyloid beta-ProteinAnimal ModelBiochemicalBioinformaticsBiological AssayBrainBrain regionCell LineComplexCustomDataData SetDegenerative DisorderDementiaDiseaseElementsExonsFrontotemporal Lobar DegenerationsFutureGene ExpressionGene Expression RegulationGene ProteinsGenesGenetic TranscriptionGenetic studyGoalsHumanImpaired cognitionIndividualIntronsKnock-inKnock-in MouseLeadMessenger RNAMethodsModelingMolecularMultiomic DataNatureNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathogenesisPathogenicityPathologicPathologyPatientsPlayProtein IsoformsProteomicsPublic HealthPublishingRNARNA SplicingRNA analysisRNA-Binding ProteinsRegulationRegulator GenesRoleSamplingSocietiesSpliceosomesTauopathiesTestingWorkbasecognitive functioncohortdesigngene productgenetic regulatory proteinin vivoindexinginduced pluripotent stem cellinnovationinsightinterdisciplinary approachmRNA ExpressionmRNA Precursormouse modelneurotoxicitynovel diagnosticsnovel therapeuticsprotein expressionresiliencerisk varianttau Proteinstau aggregationtau expressiontherapeutic developmenttooltranscriptome sequencingtreatment strategy
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mechanisms of Angiotensin I Converting Enzyme in Alzheimer's disease
血管紧张素I转换酶在阿尔茨海默病中的作用机制
- 批准号:
10568226 - 财政年份:2022
- 资助金额:
$ 309.02万 - 项目类别:
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
- 批准号:
10469445 - 财政年份:2021
- 资助金额:
$ 309.02万 - 项目类别:
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
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10264367 - 财政年份:2021
- 资助金额:
$ 309.02万 - 项目类别:
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
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10662473 - 财政年份:2021
- 资助金额:
$ 309.02万 - 项目类别:
Northwestern ADRC Non competing supplement application
西北 ADRC 非竞争性补充申请
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10577047 - 财政年份:2021
- 资助金额:
$ 309.02万 - 项目类别:
2nd Kloster Seeon Meeting on BACE Proteases in Health and Disease
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- 批准号:
9195559 - 财政年份:2016
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Molecular Neuropathology and Mechanisms of BACE1 Elevation in Alzheimer's Disease
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7248235 - 财政年份:2007
- 资助金额:
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